Substituted heteroaryl compounds and methods of use

ABSTRACT

The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof. They are useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefits of U.S. Provisional Application No.62/588,364, filed on Nov. 19, 2017, which is hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention provides novel substituted heteroaryl compounds,and salts thereof, which are useful in the treatment of proliferativedisease, autoimmune disease, allergic disease, inflammatory disease,transplantation rejection, and other diseases, in mammals. Inparticular, this invention relates to compounds that modulate theactivity of Aurora kinases, FLT4 kinase, FLT3 kinase, and/or JAK kinasesleading to the modulation of inter- and/or intracellular signaling. Thisinvention also relates to a method of using such compounds in thetreatment of proliferative disease, autoimmune disease, allergicdisease, inflammatory disease, transplantation rejection, and otherdiseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases, containing asimilar 250-300 amino acid catalytic domain, catalyze thephosphorylation of target protein substrates. It is reported that manydiseases are associated with abnormal cellular responses triggered byprotein kinase-mediated events. These diseases include benign andmalignant proliferation disorders, diseases resulting from inappropriateactivation of the immune system, allograft rejection, graft vs hostdisease, autoimmune diseases, inflammatory diseases, bone diseases,metabolic diseases, neurological and neurodegenerative diseases, cancer,cardiovascular diseases, allergies and asthma, Alzheimer's disease andhormone-related diseases. Accordingly, there has been a substantialeffort in medicinal chemistry to find protein kinase inhibitors that areeffective as therapeutic agents.

The kinases may be categorized into families by the substrates in thephosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids,etc.). Tyrosine phosphorylation is a central event in the regulation ofa variety of biological processes such as cell proliferation, migration,differentiation and survival. Several families of receptor andnon-receptor tyrosine kinases control these events by catalyzing thetransfer of phosphate from ATP to a tyrosine residue of specific cellprotein targets. Sequence motifs have been identified that generallycorrespond to each of these kinase families (Hanks et al., FASEB J.,1995, 9, 576-596; Knighton et al., Science, 1991, 253: 407-414;Garcia-Bustos et al., EMBO J., 1994, 13: 2352-2361). Some non-limitingexamples of the protein kinase include abl, Aurora, Akt, bcr-abl, BIk,Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5,CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1 R, CSK, EGFR, ErbB2, ErbB3,ErbB4, Erk, Fak, fes, Flt-3, Flt-4, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5,Fgr, Flt-1, Fps, Frk, Fyn, Hck, IGF-1 R, INS-R, JAK, KDR, Lck, Lyn, MEK,p38, PDGFR, PIK, PKC, PYK2, ros, Tie, Tie-2, TRK, Yes, and Zap70.

Aurora kinase family is a collection of highly related serine/threoninekinase that are key regulators of mitosis, essential for accurate andequal section of genomic material from parent to daught cells. Membersof the Aurora kinase family include three related kinases kown asAurora-A, Aurora-B, and Aurora-C (also known as Aurora-1, Aurora-2, andAurora-3). Despite significant sequence homology, the localization andfunctions of these kinases are largely distinct from one another(Richard D. Carvajal, et al. Clin Cancer Res., 2006, 12(23): 6869-6875;Daruka Mahadevan, et al., Expert Opin. Drug Discov., 2007, 2 (7):1011-1026).

Aurora-A is ubiquitously expressed and regulates cell cycle eventsoccurring from late S phase through M phase, including centrosomematuration, mitotic entry, centrosome separation, bipolar-spindleassembly, chromosome alignment on the metaphase plate, cytokinesis, andmitotic exit. Aurora-A protein levels and kinase activity both increasefrom late G2 through M phase, with peak activity in prometaphase. Onceactivated, Aurora-A mediates its multiple functions by interacting withvarious substrates including centrosome, transforming acidic coiled-coilprotein, cdc25b, Eg5, and centromere protein A.

Aurora-B is a chromosomal passenger protein critical for accuratechromosomal segregation, cytokinesis, protein localization to thecentromere and kinetochore, correct microtubule-kinetochore attachments,and regulation of the mitotic checkpoint. Aurora-B localizes first tothe chromosomes during prophase and then to the inner centromere regionbetween sister chromatids during prometaphase and metaphase (Zeitlin SG, et al. J. Cell Biol., 2001, 155: 1147-1157). Aurora-B participates inthe establishment of chromosomal biorientation, a condition where sisterkinetochores are linked to opposite poles of the bipolar spindle viaamphitelic attachments. The primary role of Aurora-B at this point ofmitosis is to repair incorrect microtubule-kinetochore attachments (HaufS, et al., J Cell Biol., 2003, 161: 281-294; Ditchfield C, et al., J.Cell Biol., 2003, 161: 267-280; Lan W, et al. Curr. Biol., 2004, 14:273-286). Without Aurora-B activity, the mitotic checkpoint iscompromised, resulting in increased numbers of aneuploid cells, geneticinstability, and tumorigenesis (Weaver B A, et al., Cancer Cell, 2005,8: 7-12).

Aurora-A overexpression is a necessary feature of Aurora-A inducedtumorigenesis. In cells with Aurora-A overexpression, mitosis ischaracterized by the presence of multiple centrosomes and multipolarspindles (Meraldi P et al., EMBO J., 2002, 21: 483-492). These cellsfail to undergo cytokinesis, and, with additional cell cycles,polyploidy and progressive chromosomal instability develop (Anand S, etal., Cancer Cell, 2003, 3: 51-62).

The evidence linking Aurora overexpression and malignancy proliferationdisorders, such as colon, breast, lung, pancrease, prostate, bladder,head, neck, cervix, and ovarian cancers, liver, gastric and pancreatictumors, has stimulated interest in developing Aurora inhibitors forcancer therapy. In normal cells, Aurora-A inhibition results in delayed,but not blocked, mitotic entry, centrosome separation defects resultingin unipolar mitotic spindles, and failure of cytokinesis (Marumoto T, etal., J. Biol. Chem., 2003, 278: 51786-51795). Encouraging antitumoreffects with Aurora-A inhibition were shown in three human pancreaticcancer cell lines (Panc-1, MIA PaCa-2, and SU.86.86), with growthsuppression in cell culture and near-total abrogation of tumorigenicityin mouse xenografts (Hata T, et al., Cancer Res., 2005, 65: 2899-2905).

Aurora-B inhibition results in abnormal kinetochore-microtubuleattachments, failure to achieve chromosomal biorientation, and failureof cytokinesis (Goto H, et al., J. Biol. Chem., 2003, 278:8526-30;Severson AF1 et al., Curr. Biol., 2000, 10:1162-1171). Recurrent cyclesof aberrant mitosis without cytokinesis result in massive polyploidyand, ultimately, to apoptosis (Hauf S, et al., J. Cell Biol., 2003, 161:281-294; Ditchfield C, et al., J. Cell Biol., 2003, 161: 267-80; Giet R,et al., J. Cell Biol., 2001, 152: 669-682; Murata-Hori M, Curr. Biol.,2002, 12: 894-899; Kallio M J, et al., Curr. Biol., 2002, 12: 900-905).

Inhibition of Aurora-A or Aurora-B activity in tumor cells results inimpaired chromosome alignment, abrogation of the mitotic checkpoint,polyploidy, and subsequent cell death. These in vitro effects aregreater in transformed cells than in either non-transformed ornon-dividing cells (Ditchfield C, et al., J. Cell Biol., 2003, 161:267-280). Thus, targeting Aurora may achieve in vivo selectivity forcancer. Although toxicity to rapidly dividing cell of the hematopoieticand gastrointestinal system is expected, the activity and clinicaltolerability shown in xenograft models indicates the presence of areasonable therapeutic index. Given the preclinical antitumor activityand potential for tumor selectivity, several Aurora kinase inhibitorshave been developed.

FLT3 (Flt3, FMS-related tyrosine kinase 3), also known as FLK-2 (fetalliver kinase 2) and STK-1 (human stem cell kinase 1), belongs to amember of the class III receptor tyrosine kinase (RTK-III) family thatinclude KIT, PDGFR, FMS and FLT1 (Stirewalt D L, et al., Nat. Rev.Cancer, 2003, 3:650-665; Rosnet O, et al., Genomics 1991, 9: 380-385;Yarden Y, et al., Nature, 1986, 323: 226-232; Stanley E R, et. al., J.Cell Biochem., 1983, 21:151-159; Yarden Y, et al., EMBO 1, 1987,6:3341-3351). FLT3 is a membrane-spanning protein and composed of fourdomains; an extracellular ligand-binding domains consisting of fiveimmunoglobin-like structures, a transmembrane (TM) domain, ajuxtamembrane (JM) domain and a cytoplasmic C-Terminal tyrosine kinase(TK) domain (Agnes F, et al., Gene, 1994, 145: 283-288, Scheijen B, etal., Oncogene, 2002, 21: 3314-3333).

The ligand for FLT3 (FLT3 or FL) was cloned in 1993 and shown to be aType I transmembrane protein expressed in cells of the hematopoieticbone marrow microenvironment, including bone marrow fibroblasts andother cells (Lyman S D, et al., Cell 1993, 75: 1157-1167). Both themembrane-bound and soluable forms can activate the tyrosine kinaseactivity of the receptor and stimulate growth of progenitor cells in themarrow and blood. Binding of ligand to receptor induces dimerisation ofthe receptor and activation of the kinase domains; which thenautophosphorylate and catalyse phosphorylation of substrate proteins ofvarious signal transduction pathways such as signal transducer andactivator of STATS, RAS/MAPK, PI3K, SHC, SHIP, and SHP2, which playimportant roles in cellular proliferation, differentiation, and survival(Dosil M, et al., Mol Cell Biol., 1993, 13: 6572-6585. Zhang S, BiochemBiophys Res. Commun., 1999, 254: 440-445). In addition to hemotopoieticcells, FLT3 gene is also expressed in placenta, gonads and brain (MarocN, et al. Oncogene, 1993, 8: 909-918) and also plays an importand rolein the immune response (deLapeyriere O, et al., Leukemia, 1995, 9:1212-1218).

FLT3 has also been implicated in hematopoietic disorders which arepre-malignant disorders including myeloproliferative disorders, such asthrombocythemia, essential thrombocytosis (ET), myelofibrosis (MF),chronic idiopathic myelofibrosis (IMF), and polycythemia vera (PV),pre-malignant myelodysplastic syndromes. Hematological malignanciesinclude leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease(also called Hodgkin's lymphoma), and myeloma, for instance, acutelymphocytic leukemia (ALL), acute myeloid leukemia (AML), acutepromyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL).FLT3 is overexpressed at the levels in 70-100% of cases of acute myeloidleukemias (AML), and in a high percentage of T-acute lymphocyticleukemia (ALL) cases (Griffin J D, et al., Haematol J. 2004, 5:188-190). It is also overexpressed in a smaller subset of chronicmyeloid leukemia (CML) in blast crisis. Studies have shown that theleukemic cells of B lineage ALL and AML frequently co-express FL,setting up autocrine or paracrine signaling loops that result in theconstitutive activation of FLT3 (Zheng R, et. al., Blood, 2004, 103:267-274). A high level of the FLT3 ligand is found in the serum ofpatients with Langerhans cell histocytosis and systemic lupuserythematosus, which further implicates FLT3 signaling in thedysregulation of dendritic cell progenitors in those autoimmune diseases(Rolland et al., J. Immunol., 2005, 174: 3067-3071).

Evidence is rapidly accumulating that many types of leukemias andmyeloproliferative syndromes have mutation in tyrosine kinases. FLT3mutations are one of the most frequent somatic alterations in AML,occurring in approximately ⅓ of patients. There are two types ofactivating mutations in FLT3 described in patients with leukemia. Theseinclude a spectrum of internal tandem duplications (ITD) occurringwithin the auto-inhibitory juxtamembrane domain (Nakao M, et al.,Leukemia, 1996, 10:1911-1918; Thiede C, et al., Blood, 2002,99:4326-4335), and activation loop mutations that include Asp835Tyr(D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E),Asp835Ala (D835A), Asp835Asn (D835N), Asp835 deletion and Ile836deletion (Yamamoto Yi et al., Blood 2001, 97:2434-2439; Abu-Duhier F M,et al., Br. J. Haematol., 2001, 113:983-988). Internal tandemduplication (ITD) mutations within the JM domain contribute to about17-34% of FLT3 activating mutations in AML. FLT3-ITD has also beendetected at low frequency in myelodysplastic syndrome (MDS) (Yokota S,et al., Leukemia, 1997, 11:1605-1609; Horiike S, et al., Leukemia, 1997,11:1442-1446). Both FLT3-ITD and FLT3-Asp835 mutations are associatedwith FLT3 autophosphorylation and phosphorylation of downstream targets(Mizuki M, et al. Blood, 2000, 96: 3907-3914; Mizuki M, et al., Blood,2003, 101: 3164-3173; Hayakawa F, et al., Oncogene, 2000, 19: 624-631).

Inhibitors of FLT3 are presently being studied and have reached clinicaltrials as monotherapy in relapsed or refractory AML patients, some orall of whom had FLT3 mutations. Collectively, these data suggest thatFLT3 is an attractive therapeutic target for the development of kinaseinhibitors for AML and other associated diseases.

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosinekinases that transduce cytokine-mediated signals via the JAK-STATpathway. The JAK family plays a role in the cytokine-dependentregulation of proliferation and function of cells involved in immuneresponse. Cytokines bind to their receptors, causing receptordimerization, and this enables JAKs to phosphorylate each other as wellas specific tyrosine motifs within the cytokine receptors. STATs thatrecognize these phosphotyrosine motifs are recruited to the receptor,and are then themselves activated by a JAK-dependent tyrosinephosphorylation event. Upon activation, STATs dissociate from thereceptors, dimerize, and translocate to the nucleus to bind to specificDNA sites and alter transcription.

Currently, there are four known mammalian JAK family members: JAK1(Janus kinase-1), JAK2 (Janus kinase-2), JAK3 (Janus kinase, leukocyte;JAKL; L-JAK and Janus kinase-3) and TYK2 (protein-tyrosine kinase 2).While JAK1, JAK2 and TYK2 are ubiquitously expressed, JAK3 is reportedto be preferentially expressed in natural killer (NK) cells and notresting T cells.

JAK1 is essential for signaling for certain type I and type IIcytokines. It interacts with the common gamma chain (γc) of type Icytokine receptors to elicit signals from the IL-2 receptor family, theIL-4 receptor family, the gp130 receptor family. It is also importantfor transducing a signal by type I (IFN-α/β) and type II (IFN-γ)interferons, and members of the IL-10 family via type II cytokinereceptors. Genetic and biochemical studies have shown that JAK1 isfunctionally and physically associated with the type I interferon (e g.,IFNalpha), type II interferon (e.g., IFN gamma), IL-2 and IL-6 cytokinereceptor complexes. Furthermore, characterization of tissues derivedfrom JAK1 knockout mice demonstrated critical roles for this kinase inthe IFN, IL-IO, IL-2/IL-4, and IL-6 pathways.

Expression of JAK1 in cancer cells enables individual cells to contract,potentially allowing them to escape their tumor and metastasize to otherparts of the body. Elevated levels of cytokines which signal throughJAK1 have been implicated in a number of immune and inflammatorydiseases. JAK1 or JAK family kinase inhibitors may be useful formodulating or treating in such diseases. (Kisseleva et al., Gene, 2002,285:1-24; Levy et al., Nat. Rev. Mol. Cell Biol., 2005, 3:651-662). Ahumanized monoclonal antibody targeting the IL-6 pathway (Tocilizumab)was approved by the European Commission for the treatment ofmoderate-to-severe rheumatoid arthritis (Scheinecker et al., Nat. Rev.Drug Discov., 2009, 8:273-274).

JAK2 is implicated in signaling by members of the type II cytokinereceptor family (e.g. interferon receptors), the GM-CSF receptor family,the gp130 receptor family. JAK2 signaling is activated downstream fromthe prolactin receptor. Studies have identified a high prevalence of anacquired activating JAK2 mutation (JAK2V617F) in myleoproliferativedisorders such as polycythemia vera, essential thrombocythemia andidiopathic myelofibrosis, etc. The mutant JAK2 protein is able toactivate downstream signaling in the absence of cytokine stimulation,resulting in autonomous growth and/or hypersensitivity to cytokines andis believed to play a role in driving these diseases. Additionalmutations or translocations resulting dysregulated JAK2 function havebeen described in other malignancies (Ihle J. N. and Gilliland D. G.,Curr. Opin. Genet. Dev., 2007, 17: 8; Sayyah J. and Sayeski P. P., Curr.Oncol. Rep., 2009, 11: 117). Inhibitors of JAK2 have been described tobe useful in myeloproliferative diseases (Santos et al, Blood, 2010,115:1131; Barosi G. and Rosti V., Curr. Opin. Hematol, 2009, 16:129,Atallah E. and Versotvsek S., Exp. Rev. Anticancer Ther., 2009, 9:663).

JAK3 associates exclusively with the gamma common cytokine receptorchain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21cytokine receptor complexes. JAK3 is predominantly expressed in immunecells and transduces a signal in response to its activation via tyrosinephosphorylation by interleukin receptors. Since JAK3 expression isrestricted mostly to hematopoietic cells, its role in cytokine signalingis thought to be more restricted than other JAKs. Mutations of JAK3result in severe combined immunodeficiency (SCID). (O'Shea et al., 2002,Cell, 109 (suppl.): S121-S131). Based on its role in regulatinglymphocytes, JAK3 and JAK3-mediated pathways have been targeted forimmunosuppressive indications (e.g., transplantation rejection andrheumatoid arthritis) (Baslund et al., 2005, Arthritis & Rheumatism52:2686-2692; Changelian et al., Science, 2003, 302: 875-878).

TYK2 is implicated in IFN-α, IL-6, IL-10 and IL-12 signaling.Biochemical studies and gene-targeted mice uncovered the crucial role ofTYK2 in immunity. Tyk2-deficient mice are viable and fertile but displaymultiple immunological defects, most prominently high sensitivity toinfections and defective tumor surveillance. In contrast, inhibition ofTYK2 results in increased resistance against allergic, autoimmune andinflammatory diseases. Particularly, targeting Tyk2 appears to be apromising strategy for the treatment of IL-12-, IL-23- or Type 1IFN-mediated diseases. These include but are not limited to rheumatoidarthritis, multiple sclerosis, lupus, psoriasis, psoriatic arthritis,inflammatory bowel disease, uveitis, sarcoidosis, and tumors (Shaw, M.et al., Proc. Natl. Acad. Sci. USA, 2003, 100, 11594-11599; Ortmann, R.A., and Shevach, E. M. Clin. Immunol, 2001, 98, 109-118; Watford et al,Immunol. Rev., 2004, 202: 139). (“Janus Kinase (JAK) Inhibitors inRheumatoid Arthritis.” Current Rheumatology Reviews, 2011, 7, 306-312).

A fully human monoclonal antibody targeting the shared p40 subunit ofthe IL-12 and 11-23 cytokines (Ustekinumab) was recently approved by theEuropean Commission for the treatment of moderate-to-severe plaquepsoriasis (Krueger et al., N. Engl. J. Med., 2007, 356:580-92; Reich etal., Nat. Rev. Drug Discov., 2009, 8:355-356). In addition, an antibodytargeting the IL-12 and IL-23 pathways underwent clinical trials fortreating Crohn's Disease (Mannon et al., N. Engl. J. Med., 2004, 351:2069-79).

When dysregulated, JAK-mediated responses can positively or negativelyaffect cells leading to over-activation and malignancy or immune andhematopoietic deficiencies, respectively, and suggests the utility foruse of inhibitors of JAK kinases. The JAK/STAT signaling pathway isinvolved in a variety of hyperproliferative and cancer-related processesincluding cell-cycle progression, apoptosis, angiogenesis, invasion,metastasis and evasion of the immune system (Haura et al., NatureClinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancerand Metastasis Reviews, 2003, 22, 423-434). In addition, the JAK/STATsignaling pathway is important in the genesis and differentiation ofhematopoietic cells and regulating both pro- and anti-inflammatory andimmune responses (O'Sullivan et al., Molecular Immunology, 2007,44:2497).

Therefore, the JAK/STAT pathway, and in particular all four members ofthe JAK family, are believed to play a role in the pathogenesis of theasthmatic response, chronic obstructive pulmonary disease, bronchitis,and other related inflammatory diseases of the lower respiratory tract.The JAK/STAT pathway has also been implicated to play a role ininflammatory diseases/conditions of the eye including, but not limitedto, iritis, uveitis, scleritis, conjunctivitis, as well as chronicallergic responses. Since cytokines utilize different patterns of JAKkinases (O'Sullivan et al., Mol. Immunol, 2007, 44:2497; Murray J.,Immunol, 2007, 178:2623), there may be utility for antagonists of JAKkinases with differing intra-family selectivity profiles in diseasesassociated with particular cytokines or in diseases associated withmutations or polymorphisms in the JAK/STAT pathways.

Rheumatoid arthritis (RA) is an autoimmune disease characterized bychronic joint inflammation. Patients with rheumatoid arthritis treatedwith JAK inhibitor showed that inhibition of JAK1 and JAK3 blockssignalling by multiple cytokines that are important for lymphocytefunction, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 andIL-21. (Fleischmann, R. et al., “Placebo-controlled trial of tofacitinibmonotherapy in rheumatoid arthritis.” N Engl. J. Med., 2012, 367,495-507). It was conjectured that small-molecule inhibitors thatdirectly inactivate specific JAK isoforms would also reduce not only theclinical symptoms of RA, but also suppress the upregulation of many ofthe proinflammatory cytokines that are critical in driving RA diseaseprogression. (“Inhibitors of JAK for the treatment of rheumatoidarthritis: rationale and clinical data.” Clin. Invest., 2012, 2(1),39-47).

Persistent activation of STAT3 or STATS has been demonstrated in a widespectrum of solid human tumors including breast, pancreatic, prostate,ovarian and hepatic carcinomas, as well as in the majority ofhematopoietic tumors including lymphomas and leukemias. In this context,inactivation of JAK/STAT signaling in many hematopoietic tumors resultedin inhibition of cell proliferation and/or induction of apoptosis.Although STAT3 in tumor cells can be activated by various kinases, JAK2has been shown to be the most important upstream activator mediatingSTAT3 activation in human tumor cell lines derived from various solidtumors (Mohamad Bassam Sonbol, Belal Firwana, Ahmad Zarzour, MohammadMorad, Vishal Rana and Ramon V. Tiu, Therapeutic Advances in Hematology,2013, 4(1), 15-35; Hedvat M, Huszar D, Herrmann A, Gozgit J M, SchroederA, Sheehy A, et al., Cancer Cell, 2009; 16(6): 487-97). Therefore,inhibition of JAK kinases may have a beneficial role in the therapeutictreatment of these diseases.

Clearly, protein kinase inhibitors have gathered attention as a new drugcategory for both immunosuppresion and antiinflammatory drug, and forcancer drug. Thus, new or improved agents which inhibit protein kinasessuch as Aurora inhibitors, FLT4 inhibitors, FLT3 inhibitors and Januskinases inhibitors are continually needed that act as immunosuppressiveagents for organ transplants, and antitumor agents, as well as agentsfor the prevention and treatment of autoimmune diseases (e.g., multiplesclerosis, psoriasis, rheumatoid arthritis, asthma, type I diabetes,inflammatory bowel disease, Crohn's disease, polycythemia vera,essential thrombocythemia, myelofibrosis, autoimmune thyroid disorders,Alzheimer's disease), diseases involving a hyperactive inflammatoryresponse (e.g., eczema), allergies, chronic obstructive pulmonarydisease, bronchitis, cancer (e.g., prostate, acute myelogenous leukemia,chronic myelogenous leukemia, acute lymphocytic leukemia, leukemia,multiple myeloma), and some immune reactions (e.g., skin rash or contactdermatitis or diarrhea) caused by other therapeutics, to name a few. Thecompounds, compositions and methods described herein are directed towardthese needs and other ends.

SUMMARY OF THE INVENTION

The invention provides compounds that inhibit, regulate, and/or modulateone or more protein kinases such as JAK, FLT4, FLT3 and/or Aurorakinases activities, and are useful for treating proliferative diseases,autoimmune diseases, allergic diseases, inflammatory diseases,transplantation rejections, and/or their co-morbidities. This inventionalso provides methods of making the compound, methods of using suchcompounds in the treatment of said diseases in mammals, especially inhumans, and pharmaceutical compositions containing these compounds. Thecompounds or the pharmaceutical compositions disclosed herein havebetter prospects for clinical application. Compared with the similarcompounds, the compounds disclosed herein have better pharmacologicalactivitvites, pharmacokinetic properties, physical and chemicalproperties and less toxicity. In particular, the compounds of thepresent invention display potent inhibitory activities against targetkinases, and optimized selectivity and exhibit good absorption and highbioavailability in vivo pharmacokinetic experiments. In addition, thecompounds or the pharmaceutical compositions disclosed herein have nocardiac toxicity.

Specifically, in one aspect, provided herein is a compound havingFormula (I):

or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug thereof, wherein each ofW, A, T, Z and R¹ is as defined herein.

In one embodiment, W is a 4-7 membered saturated monocyclicheterocyclylene or saturated monocyclic C₅-C₇ carbocyclylene, wherein Wis optionally substituted by 1, 2, 3, 4 or 5 R² groups;

T is C₆-C₁₂ aryl or 5-12 membered heteroaryl, wherein T is optionallysubstituted by 1, 2, 3, 4 or 5 R³ groups;

A is an optionally substituted 9-membered heteroaryl group, havingFormula (A-1), (A-2), (A-3)(A-4), (A-5) or (A-6):

wherein each V₁ and V₂ is independently CR⁴ or N;

each U₁, U₂ and U₃ is independently CR⁴ or N;

each of U₄ and U₆ is independently CR⁴, N, NR⁵, O or S;

U₅ is independently CR⁴, O or S;

wherein at least one of V₁, V₂, U₃, U₄, U₅ and U₆ is not CR⁴;

Z is H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl or 3-12 membered heterocyclyl,wherein each of the C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyland 3-12 memberedheterocyclylis optionally substituted by 1, 2, 3, 4 or 5 R⁹ groups;

R¹ is H, F, Cl, Br, I, NO₂, N₃, CN, C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl,C₃-C₁₂ cycloalkyl or 3-12 membered heterocyclyl, wherein each of theC₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₃-C₁₂ cycloalkyl and 3-12 memberedheterocyclyl is optionally substituted by 1, 2 or 3 R⁹ groups;

each R² and R³ is independently F, Cl, Br, I, NO₂, N₃, CN, OH, C₁-C₁₂alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl,5-12 membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl),—(C₁-C₄ alkylene)-(5-12 membered heteroaryl), —(CR⁶R⁷)_(n)—OR^(c),—(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)C(═O)R⁸, —(CR⁶R⁷)_(n)OC(═O)R⁸,—O(CR⁶R⁷)_(n)—R^(c), —(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸,—(CR⁶R⁷)_(n)C(═O)OR^(c), —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b),—N(R^(c))C(═O)NR^(a)R^(b), —N(R^(c))S(═O)_(m)NR^(a)R^(b),—C(═O)N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n)S(═O)_(m)R⁸, —N(R^(c))S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₁₂ alkyl,C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl)and —(C₁-C₄ alkylene)-(5-12 membered heteroaryl) is optionallyindependently substituted by 1, 2, 3, 4 or 5 R⁹ groups;

each R⁴ is independently H, F, Cl, Br, I, NO₂, N₃, CN, C₁-C₁₂ alkyl,C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)C(═O)R⁸, —(CR⁶R⁷)_(n)OC(═O)R⁸, —O(CR⁶R⁷)_(n)—R^(c),—(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —N(R^(c))C(═O)NR^(a)R^(b),—N(R^(c))S(═O)_(m)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸,—N(R^(c))S(═O)_(m)R⁸ or —(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), or twoadjacent R⁴ taken together with the carbon atoms to which they areattached form a C₃-C₁₂ carbocycle or 3-12 membered heterocycle, whereineach of the C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12membered heterocyclyl, 5-12 membered heteroaryl, C₃-C₁₂ carbocycle and3-12 membered heterocycle is optionally independently substituted by 1,2, 3, 4 or 5 R⁹ groups;

each R⁵ is independently absent, or H, C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl,C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl,C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl,—(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)C(═O)R⁸,—(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₁₂ alkyl,C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl and 5-12membered heteroaryl is optionally independently substituted by 1, 2 or 3R⁹ groups;

each R⁶ and R⁷ is independently H, F, Cl, Br, I, NO₂, N₃, CN, C₁-C₁₂alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl or 5-12 memberedheteroaryl, or R⁶ and R⁷ taken together with the carbon atom to whichthey are attached form a C₃-C₁₂ carbocycle or 3-12 membered heterocycle,wherein each of the C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 memberedheterocyclyl, 5-12 membered heteroaryl, C₃-C₁₂ carbocycle and 3-12membered heterocycle is optionally independently substituted by 1, 2 or3 R⁹ groups;

each R⁸ is independently C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 memberedheterocyclyl, 5-12 membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂cycloalkyl), —(C₁-C₄ alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄alkylene)-(C₆-C₁₂ aryl) or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl),wherein each R⁸ is optionally substituted by 1, 2 or 3 R⁹ groups;

each R⁹ is independently F, Cl, Br, I, CN, NO₂, N₃, —OH, —NH₂, C₁-C₁₂,alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12 memberedheteroaryl, —NH(C₁-C₁₂ alkyl), —NH(CH₂)_(n)—(C₃-C₁₂ cycloalkyl),—NH(CH₂)_(n)—(C₆-C₁₂ aryl), —NH(CH₂)_(n)-(3-12 membered heterocyclyl),—NH(CH₂)_(n)-(5-12 membered heteroaryl), —N(C₁-C₁₂ alkyl)₂,—N[(CH₂)_(n)—(C₃-C₁₂ cycloalkyl)]₂, —N[(CH₂)_(n)—(C₆-C₁₂ aryl)]₂,—N[(CH₂)_(n)-(3-12 membered heterocyclyl)]₂, —N[(CH₂)_(n)-(5-12 memberedheteroaryl)]₂, —O(C₁-C₁₂ alkyl), —O(CH₂)_(n)—(C₃-C₁₂cycloalkyl),—O(CH₂)_(n)—(C₆-C₁₂ aryl), —O(CH₂)_(n)-(3-12 membered heterocyclyl) or—O(CH₂)_(n)-(5-12 membered heteroaryl);

each R^(a), R^(b) and R^(c) is independently H, C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, —(C₁-C₄alkylene)-(C₃-C₆ cycloalkyl), 4-7 membered heterocyclyl, —(C₁-C₄alkylene)-(4-7 membered heterocyclyl), C₆-C₁₂ aryl, —(C₁-C₄alkylene)-(C₆-C₁₂ aryl), 5-12 membered heteroaryl or —(C₁-C₄alkylene)-(5-12 membered heteroaryl), or R^(a) and R^(b) taken togetherwith the nitrogen atom to which they are attached form a 4-7 memberedheterocycle, wherein each of the C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, —(C₁-C₄ alkylene)-(C₃-C₆cycloalkyl), 4-7 membered heterocyclyl, —(C₁-C₄ alkylene)-(4-7 memberedheterocyclyl), C₆-C₁₂ aryl, —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl), 5-12membered heteroaryl, —(C₁-C₄ alkylene)-(5-12 membered heteroaryl) and4-7 membered heterocycle is optionally independently substituted by 1,2, 3 or 4 substitutents independently selected from F, Cl, Br, CN, N₃,—OH, —NH₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆alkylamino;

each n is independently 0, 1, 2, 3 or 4; and

each m is independently 1 or 2.

In another embodiment, W is a saturated monocyclic heterocyclylenederived from one of the following heterocyclic compounds:

and wherein W is optionally substituted by 1, 2 or 3 R² groups.

In one embodiment, W is:

and wherein W is optionally substituted by 1, 2 or 3 R² groups.

In another embodiment, T is phenyl or 5-6 membered heteroaryl, wherein Tis optionally substituted by 1, 2, 3 or 4 R³ groups.

In one embodiment, T is phenyl, pyridyl, pyridonyl, pyrimidinyl,pyrimidonyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, thiazolyl,isothiazolyl, tetrazolyl, triazolyl, thienyl, pyrazolyl, oxadiazolyl,thiadiazolyl or triazinyl, wherein T is optionally substituted by 1, 2or 3 R³ groups.

In another embodiment, A is:

wherein each CH atom in A is optionally independently substituted by aR⁴ group; each NH in A is optionally independently substituted by a R⁵group.

In one embodiment, Z is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl or 4-7 memberedheterocyclyl, wherein each of the C₁-C₆ alkyl, C₃-C₆ cycloalkyl and 4-7membered heterocyclyl is optionally substituted by 1, 2 or 3 R⁹ groups.

In another embodiment, Z is H, methyl, ethyl, n-propyl, i-propyl,cyclopropyl or cyclobutyl.

In one embodiment, R¹ is H, F, Cl, Br, NO₂, N₃, CN, C₁-C₄ alkyl, C₁-C₄heteroalkyl, C₃-C₆ cycloalkyl or 4-7 membered heterocyclyl, wherein eachof the C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₃-C₆ cycloalkyl and 4-7 memberedheterocyclyl is optionally substituted by 1, 2 or 3 R⁹ groups.

In another embodiment, each R² and R³ is independently F, Cl, Br, NO₂,N₃, CN, OH, C₁-C₄ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 memberedheterocyclyl, 5-6 membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c),—(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)OC(═O)R⁸,—(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n))C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸,—N(R_(n))S(═O)_(m)R⁸ or —(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein eachof the C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 memberedheterocyclyl and 5-6 membered heteroaryl is optionally independentlysubstituted by 1, 2 or 3 R⁹ groups.

In one embodiment, each R⁴ is independently H, F, Cl, Br, NO₂, N₃, CN,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸,—(CR⁶R⁷)_(n)C(═O)OR^(c), —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b),—(CR⁶R⁷)_(n)S(═O)_(m)R⁸, —N(R^(c))S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), or two adjacent R⁴ taken together withthe carbon atoms to which they are attached form a C₃-C₆ carbocycle or4-7 membered heterocycle, wherein each of the C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl,C₃-C₆ carbocycle and 4-7 membered heterocycle is optionallyindependently substituted by 1, 2 or 3 R⁹ groups.

In another embodiment, each R⁴ is independently H, F, Cl, Br, N₃, CN,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃,—CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,—(CR⁶R⁷)_(n)C(═O)OR^(c) or —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), or two adjacentR⁴ taken together with the carbon atoms to which they are attached forma C₄-C₆ carbocycle or 4-7 membered heterocycle, wherein each of themethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃,—CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₄-C₆ carbocycleand 4-7 membered heterocycle is optionally independently substituted by1, 2 or 3 R⁹ groups.

In one embodiment, each R⁵ is independently absent, or H, C₁-C₆ alkyl,C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 memberedheteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl and 5-6 memberedheteroaryl is optionally independently substituted by 1, 2 or 3 R⁹groups.

In another embodiment, each R⁵ is independently absent, or H, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,—CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃, —CH₂C(CH₃)₂OH,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl,pyrrolidinyl, morpholinyl, piperazinyl, —(CR⁶R⁷)_(n)C(═O)OR^(c) or—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), wherein each of the methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —CH₂OH, —CH₂CH₂OH,—CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃, —CH₂C(CH₃)₂OH, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl,morpholinyl and piperazinyl is optionally independently substituted by1, 2 or 3 R⁹ groups.

In one embodiment, each R⁶ and R⁷ is independently H, F, Cl, Br, CN,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl or 5-6 memberedheteroaryl, or R⁶ and R⁷ taken together with the carbon atom to whichthey are attached form a C₃-C₆ carbocycle or 4-7 membered heterocycle,wherein each of the C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6membered heteroaryl, C₃-C₆ carbocycle and 4-7 membered heterocycle isoptionally independently substituted by 1, 2 or 3 R⁹ groups.

In another embodiment, each R⁸ is independently C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7membered heterocyclyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆cycloalkyl), —(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃alkylene)-phenyl or —(C₁-C₃ alkylene)-(5-6 membered heteroaryl), whereineach R⁸ is optionally substituted by 1, 2 or 3 R⁹ groups.

In one embodiment, each R⁹ is independently F, Cl, Br, CN, N₃, —NH₂,—OH, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl,—NH(C₁-C₆ alkyl), —NH(CH₂)_(n)—(C₃-C₆ cycloalkyl), —NH(CH₂)_(n)-phenyl,—NH(CH₂)_(n)-(4-7 membered heterocyclyl), —NH(CH₂)_(n)-(5-6 memberedheteroaryl), —N(C₁-C₆ alkyl)₂, —N[(CH₂)_(n)—(C₃-C₆ cycloalkyl)]₂,—N[(CH₂)_(n)-phenyl]₂, —N[(CH₂)_(n)-(4-7 membered heterocyclyl)]₂,—N[(CH₂)_(n)-(5-6 membered heteroaryl)]₂, —O(C₁-C₆ alkyl),—O(CH₂)_(n)—(C₃-C₆ cycloalkyl), —O(CH₂)_(n)-phenyl, —O(CH₂)_(n)-(4-7membered heterocyclyl) or —O(CH₂)_(n)-(5-6 membered heteroaryl).

In another embodiment, each R^(a), R^(b) and R^(c) is independently H,methyl, ethyl, n-propyl, isopropyl, n-butyl, C₁-C₄ heteroalkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl,—(C₁-C₂ alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₂ alkylene)-(4-7 memberedheterocyclyl), —(C₁-C₂ alkylene)-phenyl or —(C₁-C₂ alkylene)-(5-6membered heteroaryl), or R^(a) and R^(b) taken together with thenitrogen atom to which they are attached form azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl, wherein each of the methyl, ethyl, n-propyl,isopropyl, n-butyl, C₁-C₄ heteroalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C₁-C₂alkylene)-(C₃-C₆ cycloalkyl), 4-6 membered heterocyclyl, —(C₁-C₂alkylene)-(4-7 membered heterocyclyl), phenyl, —(C₁-C₂ alkylene)-phenyl,5-6 membered heteroaryl, —(C₁-C₂ alkylene)-(5-6 membered heteroaryl),azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl is optionallyindependently substituted by 1, 2 or 3 substitutents independentlyselected from F, Cl, CN, N₃, —OH, —NH₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy and C₁-C₄ alkylamino.

In another aspect, provided herein is a pharmaceutical compositioncomprising the compound disclosed herein, and a pharmaceuticallyacceptable excipient, carrier, adjuvant, vehicle or a combinationthereof.

In one embodiment, the pharmaceutical composition disclosed hereinfurther comprising a therapeutic agent selected from the groupconsisting of chemotherapeutic agents, anti-proliferative agents,phosphodiesterase 4 (PDE4) inhibitors, β₂-adrenoreceptor agonists,corticosteroids, non-steroidal GR agonists, anticholinergic agents,antihistamine, anti-inflammatory agents, immunosuppressants,immunomodulators, agents for treating atherosclerosis, agents fortreating pulmonary fibrosis and combinations thereof.

In another aspect, provided herein is a method of preventing, managing,treating or lessening the severity of a protein kinase-mediated diseasein a patient by administering to the patient with the compound disclosedherein or the pharmaceutical composition disclosed herein. In oneembodiment, the protein kinase-mediated disease is JAK-mediated disease,FLT4-mediated disease, FLT3-mediated disease or Aurora-mediated disease.

In another embodiment, the protein kinase-mediated disease is aproliferative disease, an autoimmune disease, an allergic disease, aninflammatory disease, a transplantation rejection or cancer.

In another embodiment, the protein kinase-mediated disease is cancer(e.g. colorectal cancer, hodgkin lymphoma, non-hodgkin lymphoma, gastriccancer, esophageal cancer, breast cancer, lung cancer, hepaticcarcinoma, prostate cancer, pancreatic cancer, thyroid cancer, bladdercancer, kidney cancer, brain tumor, cancer of the head and neck, cancerof the CNS, malignant glioma, non-small cell lung cancer, cervicalcancer, testicular cancer, multiple myeloma, lymphoma, malignantlymphoma, small cell lung cancer, neuroblastoma, neuroendocrine tumor,medullary thyroid carcinoma, melanoma, retinoblastoma, metrocarcinoma,ovarian cancer, acute myeloid leukemia (AML), acute lymphocytic leukemia(ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia(CLL)), primary gigantic globulin hematic disease, mononuclear cellleukemia, sezary syndrome, infectious mononucleosis, colitis,pancreatitis, atherosclerosis, pulmonary fibrosis, polycythemia vera,essential thrombocytosis, myelofibrosis, chronic obstruction pulmonarydisease (COPD), asthma, systemic lupus erythematosis, cutaneous lupuserythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome,psoriasis, type I diabetes mellitus, allergic airway disease, sinusitis,eczema, hives, food allergies, allergies to insect venom, inflammatorybowel syndrome, Chron's disease, rheumatoid arthritis, juvenilearthritis, psoriatic arthritis, organ transplant rejection, tissuetransplant rejection or cell transplant rejection.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in preventing, managing, treatingor lessening the severity of a protein kinase-mediated disease in apatient.

In another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for preventing, managing, treating or lessening a proteinkinase-mediated disease.

In another aspect, provided herein is a method of modulating theactivity of a protein kinase with the compound or the pharmaceuticalcomposition disclosed herein. In one embodiment, the protein kinase isJAK kinases, FLT4 kinase, FLT3 kinase, Aurora kinases or a combinationthereof.

In another embodiment, wherein the protein kinase is JAK1 kinase, JAK2kinase, JAK3 kinase, TYK2 kinase, Aurora-A kinase, Aurora-B kinase, FLT4kinase, FLT3 kinase or a combination thereof.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in modulating the activity of aprotein kinase.

In still another aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for modulating the activity of a protein kinase.

In another aspect, provided herein are methods for preparation,separation and purification of the compounds represented by Formula (I).Biological test results provided herein indicate that the compounds ofthe inventioncan be used as preferable inhibitors of protein kinases,especially, JAK kinases, such as JAK1 kinase and JAK2 kinase.

Any embodiment disclosed herein can be combined with other embodimentsas long as they are not contradictory to one another, even though theembodiments are described under different aspects of the invention. Inaddition, any technical feature in one embodiment can be applied to thecorresponding technical feature in other embodiment as long as they arenot contradictory to one another, even though the embodiments aredescribed under different aspects of the invention.

The foregoing merely summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION Definitions and GeneralTerminology

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. The invention is intended to cover allalternatives, modifications, and equivalents which may be includedwithin the scope of the present invention as defined by the claims. Oneskilled in the art will recognize many methods and materials similar orequivalent to those described herein, which could be used in thepractice of the present invention. The present invention is in no waylimited to the methods and materials described herein. In the event thatone or more of the incorporated literature, patents, and similarmaterials differs from or contradicts this application, including butnot limited to defined terms, term usage, described techniques, or thelike, this application controls. It is further appreciated that certainfeatures of the invention, which are, for clarity, described in thecontext of separate embodiments, can also be provided in combination ina single embodiment. Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one skilled in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75^(th) Ed. 1994.Additionally, general principles of organic chemistry are described inSorrell et al., “Organic Chemistry”, University Science Books,Sausalito: 1999, and Smith et al., “March's Advanced Organic Chemistry”,John Wiley & Sons, New York: 2007, all of which are incorporated byreference in their entireties.

The grammatical articles “a”, “an” and “the”, as used herein, areintended to include “at least one” or “one or more” unless otherwiseindicated herein or clearly contradicted by the context. Thus, thearticles are used herein to refer to one or more than one (i.e. at leastone) of the grammatical objects of the article. By way of example, “acomponent” means one or more components, and thus, possibly, more thanone component is contemplated and may be employed or used in animplementation of the described embodiments.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, “patient” refers to a human (including adults andchildren) or other animal. In one embodiment, “patient” refers to ahuman.

The term “comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

“Stereoisomers” refers to compounds which have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include enantiomer, diastereomers,conformer (rotamer), geometric (cisltrans) isomer, atropisomer, etc.“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties or biological activities. Mixture ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography such as HPLC.

Stereochemical definitions and conventions used herein generally followParker et al., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York and Eliel et al., “Stereochemistry ofOrganic Compounds”, John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes D and L, or R and S, are usedto denote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or 1 meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. A specific stereoisomer may be referred toas an enantiomer, and a mixture of such stereoisomers is called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon or the like) of the compound(s)disclosed herein can be present in racemic or enantiomerically enriched,for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration. If the compound contains a disubstitutedcycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric isomers, enantiomers, diastereomers, forexample, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by methods known to those skilled inthe art, e.g., by separation of the diastereomeric salts thereof.Racemic products can also be resolved by chiral chromatography, e.g.,high performance liquid chromatography (HPLC) using a chiral adsorbent.Preferred enantiomers can also be prepared by asymmetric syntheses. See,for example, Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis(2^(nd) Ed. Robert et al., Elsevier, Oxford, UK, 2012); Eliel et al.,Stereochemistry of Carbon Compounds (McGraw-Hill, N.Y., 1962); and Wilenet al., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972). ChiralSeparation Techniques: A Practical Approach (Subramanian, G. Ed.,Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.Where tautomerization is possible (e.g. in solution), a chemicalequilibrium of tautomers can be reached. For example, proton tautomers(also known as prototropic tautomers) include interconversions viamigration of a proton, such as keto-enol and imine-enamineisomerizations. Valence tautomers include interconversions byreorganization of some of the bonding electrons. A specific example ofketo-enol tautomerization is the interconversion of pentane-2,4-dioneand 4-hydroxypent-3-en-2-one tautomers. Another example oftautomerization is phenol-keto tautomerization. A specific example ofphenol-keto tautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers. Unless otherwise stated, all tautomericforms of the compounds disclosed herein are within the scope of theinvention.

As described herein, compounds disclosed herein may optionally besubstituted with one or more substituents, such as those illustratedbelow, or as exemplified by particular classes, subclasses, and speciesof the invention. It will be appreciated that the phrase “optionallysubstituted” is used interchangeably with the phrase “substituted orunsubstituted”. The term “optional” or “optionally” means that thesubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. In general, the term“substituted” refers to the replacement of one or more hydrogen radicalsin a given structure with the radical of a specified substituent. Unlessotherwise indicated, an optionally substituted group may have asubstituent at each substitutable position of the group. When more thanone position in a given structure can be substituted with more than onesubstituent selected from a specified group, the substituent may beeither the same or different at each position.

Some non-limiting examples of the substituents include D, F, Cl, Br, I,CN, N₃, —NO₂, —OH, —SH, —NH2, —(CR⁶R⁷)_(n)—OR^(c),—(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)C(═O)R⁸, —(CR⁶R⁷)_(n)OC(═O)R⁸,—O(CR⁶R⁷)_(n)—R^(c), —(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸,—(CR⁶R⁷)_(n)C(═O)OR^(c), —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b),—N(R^(c))C(═O)NR^(a)R^(b), —N(R^(c))S(═O)_(m)NR^(a)R^(b),—C(═O)N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n)S(═O)_(m)R⁸, —N(R^(c))S(═O)_(m)R⁸,—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), alkyl, heteroalkyl, haloalkyl,alkenyl, alkynyl, alkoxyl, hydroxyalkyl, alkylthiolyl, alkylamino,aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and the like,wherein each R⁶, R⁷, R⁸, R^(a), R^(b), R^(c), m and n carries thedefinitions described herein.

At various places in the present specification, substituents ofcompounds disclosed herein are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C1-C6 alkyl” is specifically intended to individuallydisclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

The term “M-M₁ membered” refers to consisted of M to M₁ ring atoms,wherein M-M₁ represents M, M₁ and the integers between M and M₁, thering atoms include carbon atom and/or heteratoms such as O, N, S, P, andso on. For example, “6-10 membered heteroaryl” refers to heteroarylconsisted of 6, 7, 8, 9 or 10 atoms.

At various places in the present specification, linking substituents aredescribed. Where the structure clearly requires a linking group, theMarkush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “alkyl” or “alkyl group” refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms,wherein the alkyl radical may be optionally substituted independentlywith one or more substituents described below. Unless otherwisespecified, the alkyl group contains 1-20 carbon atoms. In oneembodiment, the alkyl group contains 1-12 carbon atoms. In anotherembodiment, the alkyl group contains 1-6 carbon atoms. In anotherembodiment, the alkyl group contains 3-6 carbon atoms. In still anotherembodiment, the alkyl group contains 1-4 carbon atoms. In yet anotherembodiment, the alkyl group contains 1-3 carbon atoms. The alkyl radicalmay be optionally substituted independently with one or moresubstituents described herein.

Some non-limiting examples of the alkyl group include methyl (Me, —CH₃),ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl(i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, tert-butyl, —C(CH₃)₃),1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃),3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 2,2-dimethylbutyl (neopentyl,—CH₂CH(CH₃)₂CH₃), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkylene” refers to a saturated divalent or multivalenthydrocarbon group derived from a straight or branched chain saturatedhydrocarbon by the removal of two or more hydrogen atoms. Unlessotherwise specified, the alkylene group contains 1-12 carbon atoms. Inone embodiment, the alkylene group contains 1-6 carbon atoms. In anotherembodiment, the alkylene group contains 1-4 carbon atoms. In anotherembodiment, the alkylene group contains 0-4 carbon atoms. In anotherembodiment, the alkylene group contains 0-3 carbon atoms. In anotherembodiment, the alkylene group contains 1-3 carbon atoms. In stillanother embodiment, the alkylene group contains 0-2 carbon atoms. Instill another embodiment, the alkylene group contains 1-2 carbon atoms.The alkylene group contains 0 carbon atom refers to a single bond. Thealkylene group is exemplified by methylene (—CH₂—), ethylidene(—CH₂CH₂—), isopropylidene (—CH(CH₃)CH₂—), and the like.

The term “heteroalkyl” refers to alkyl chain inserted with one or moreheteroatoms, wherein the alkyl and heteroatom are as defined herein. Theheteroalkyl attached to the other groups through an carbon atom. Unlessotherwise specified, heteroalkyl groups contain 1-12 carbon atoms. Inother embodiments, heteroalkyl groups contain 1-8 carbon atoms. In stillother embodiments, heteroalkyl groups contain 1-6 carbon atoms; and inyet other embodiments, heteroalkyl groups contain 1-4 carbon atoms. Inother embodiments, heteroalkyl groups contain 1-3 carbon atoms. Somenon-limiting examples of the heteroalkyl group include —CH₂OCH₃,—CH₂CH₂OCH₂CH₃, —CH₂CH₂OCH₃, —CH₂S CH₃, —CH₂N(CH₃)₂, —CH₂OCH₂(CH₃)₂,—CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃, and the like.

The term “heteroalkylene” refers to a group derived from a heteroalkylby the removal of two or more hydrogen atoms. The heteroalkyleneattached to the other groups through carbon atoms. Unless otherwisespecified, the heteroalkylene group contains 1-12 carbon atoms. In oneembodiment, the heteroalkylene group contains 1-6 carbon atoms. Inanother embodiment, the heteroalkylene group contains 1-4 carbon atoms.In another embodiment, the heteroalkylene group contains 1-3 carbonatoms. Some non-limiting examples of the heteroalkylene include—CH₂OCH₂—, —CH₂CH₂OCH₂CH₂—, —CH₂CH₂OCH₂—, —CH₂S CH₂—, —CH₂N(CH₃) CH₂—,—CH₂OCH₂(CH₃)CH₂—, —CH₂CH₂NHCH₂—, CH₂CH₂NHCH₂CH₂—, and the like.

The term “alkenyl” refers to a linear or branched-chain monovalenthydrocarbon radical of 2 to 12 carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations. Inone embodiment, the alkenyl group contains 2-8 carbon atoms. In anotherembodiment, the alkenyl group contains 2-6 carbon atoms. In stillanother embodiment, the alkenyl group contains 2-4 carbon atoms. Somenon-limiting examples of the alkenyl group include ethylenyl or vinyl(—CH═CH₂), allyl (—CH₂CH═CH₂), and the like. The alkenyl radical may beoptionally substituted independently with one or more substituentsdescribed herein.

The term “alkynyl” refers to a linear or branched-chain monovalenthydrocarbon radical of 2 to 12 carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. In one embodiment, the alkynyl groupcontains 2-8 carbon atoms. In another embodiment, the alkynyl groupcontains 2-6 carbon atoms. In still another embodiment, the alkynylgroup contains 2-4 carbon atoms. Some non-limiting examples of thealkynyl group include ethynyl (—C≡CH), propargyl (—CH2C≡CH), propynyl(—C≡C—CH3), and the like.

The term “alkoxy” refers to an alkyl group, as previously defined,attached to the principal carbon atom through an oxygen atom. Unlessotherwise specified, the alkoxy group contains 1-12 carbon atoms. In oneembodiment, the alkoxy group contains 1-6 carbon atoms. In anotherembodiment, the alkoxy group contains 1-4 carbon atoms. In still anotherembodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxyradical may be optionally substituted independently with one or moresubstituents described herein.

Some non-limiting examples of alkoxy groups include methoxy (MeO,—OCH₃), ethoxy (EtO, —OCH₂CH₃), 1-propoxy (n-PrO, n-propoxy,—OCH₂CH₂CH₃), 2-propoxy (i-PrO, i-propoxy, —OCH(CH₃)₂), 1-butoxy (n-BuO,n-butoxy, —OCH₂CH₂CH₂CH₃), 2-methyl-1-propoxy (i-BuO, i-butoxy,—OCH₂CH(CH₃)₂), 2-butoxy (s-BuO, s-butoxy, —OCH(CH₃)CH₂CH₃),2-methyl-2-propoxy (t-BuO, tert-butoxy, —OC(CH₃)₃), 1-pentoxy(n-pentoxy, —OCH₂CH₂CH₂CH₂CH₃), 2-pentoxy (—OCH(CH₃)CH₂CH₂CH₃),3-pentoxy (—OCH(CH₂CH₃)₂), 2-methyl-2-butoxy (—OC(CH₃)₂CH₂CH₃),3-methyl-2-butoxy (—OCH(CH₃)CH(CH₃)₂), 3-methyl-1-butoxy(—OCH₂CH₂CH(CH₃)₂), 2-methyl-1-butoxy (—OCH₂CH(CH₃)CH₂CH₃), and thelike.

The term “haloalkyl”, “haloalkenyl” or “haloalkoxy” refers to alkyl,alkenyl, or alkoxy, as the case may be, substituted with one or morehalogen atoms. Some non-limiting examples of haloalkyl and haloalkoxyare include trifluoromethyl (—CF₃), trifluoromethoxy (—OCF₃),difluoroethyl (—CH₂CHF₂, —CF₂CH₃, —CHFCH₂F), trifluoroethyl (—CH₂CF₃,—CF₂CH₂F, —CFHCHF₂) and the like.

The term “hydroxyalkyl” and “hydroxyalkoxy” refers to alkyl or alkoxy,as the case may be, substituted with one or more hydroxy. Somenon-limiting examples of hydroxyalkyl and hydroxyalkoxy includehydroxymethyl (—CH₂OH), hydroxyethyl (—CH₂CH₂OH, —CHOHCH₃),hydroxypropyl (—CH₂CH₂CH₂OH, —CH₂CHOHCH₃, —CHOHCH₂CH₃), hydroxymethoxy(—OCH₂OH) and the like.

The term “carbocycle”, “carbocyclyl” or “carbocyclic ring” refers to amonovalent or multivalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclicor tricyclic ring system. The carbobicyclyl refers to a spirocarbobicyclyl, a fused carbobicyclyl or a bridged carbobicyclyl. Somenon-limiting examples of carbocycle group include cycloalkyl,cycloalkenyl, and cycloalkynyl. In one embodiment, the carbocyclecontains 3-12 carbon atoms. In another embodiment, the carbocyclecontains 3-8 carbon atoms. In another embodiment, the carbocyclecontains 5-7 carbon atoms. In another embodiment, the carbocyclecontains 3-6 carbon atoms. In another embodiment, the carbocyclecontains 4-6 carbon atoms. Further non-limiting examples of carbocyclegroup include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, and the like.

The term “cycloalkyl” refers to a monovalent or multivalent saturatedring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclicring system. The bicycloalkyl refers to spiro bicycloalkyl, fusedbicycloalkyl or bridged bicycloalkyl. In one embodiment, the cycloalkylcontains 3-12 carbon atoms. In another embodiment, the cycloalkylcontains 3-8 carbon atoms. In another embodiment, the cycloalkylcontains 3-6 carbon atoms. In another embodiment, the cycloalkyl refersto a C₇-C₁₂ bicycloalkyl which contains 7-12 carbon atoms. The C₇-C₁₂bicycloalkyl includes C₇-C₁₂ spiro, C₇-C₁₂ fused bicycloalkyl and C₇-C₁₂bridged bicycloalkyl. In yet another embodiment, cycloalkyl may be aC₈-Ciibicycloalkyl which refers to C₈-C₁₁ spiro, C₈-C₁₁ fusedbicycloalkyl and C₈-C₁₁ bridged bicycloalkyl. Some non-limiting examplesof cycloalkyl, include the C₃-C₆ cycloalkyl which refers to cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl radical may beoptionally substituted independently with one or more substituentsdescribed herein.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic ring” as usedinterchangeably herein refers to a monovalent or multivalent, saturatedor partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclicring containing 3-12 ring atoms of which at least one ring atom isselected from nitrogen, sulfur and oxygen, and which may, unlessotherwise specified, be carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. The heterocyclyl containssaturated heterocyclyl (i.e. heterocycloalkyl) and partially unsaturatedheterocyclyl. Some non-limiting examples of heterocyclyl includeoxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl,3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl,2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, dithianyl,homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl (e.g.1,4-oxazepinyl, 1,2-oxazepinyl), diazepinyl (e.g. 1,4-diazepinyl,1,2-diazepinyl), dioxpinyl (e.g. 1,4-dioxpinyl, 1,2-dioxpinyl),thiazepinyl (e.g. 1,4-thiazepinyl, 1,2-thiazepinyl),2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-azaspiro[4.4]nonanyl,1,6-dioxaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl,8-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl,3-azaspiro[5.5]undecanyl, 2-azaspiro[5.5]undecanyl,octahydro-1H-isoindolyl, octahydrocyclopenta[c]pyrrolyl, indolinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxo lyl,hexahydrofuro[3,2-b]furanyl, decahydroisoquinolinyl, and the like. Somenon-limiting examples of heterocyclyl wherein —CH₂— group is replaced by—C(═O)— moiety are 1,1-dioxide isothiazolidin-2-yl,pyrrolidin-2-one-1-yl, imidazolidin-2-one-1-yl, oxazolidin-2-one-3-yl,2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl and3,5-dioxopiperidinyl. Some non-limiting examples of heterocyclyl whereinthe ring sulfur atom is oxidized are sulfolanyl,1,1-dioxotetrahydrothiophenyl, 1,1-dioxothiomorpholinyl,1,1-dioxotetrahydro-2H-thiopyranyl. The heterocyclyl group may beoptionally substituted with one or more substituents described herein.

In one embodiment, heterocyclyl may be a 3-8 membered heterocyclyl,which refers to a monovalent or multivalent, saturated or partiallyunsaturated, monocyclic ring containing 3-8 ring atoms, of which atleast one ring atom is selected from nitrogen, sulfur and oxygen, and ofwhich may, unless otherwise specified, be carbon or nitrogen linked, andof which a —CH₂— group can optionally be replaced by a —C(═O)— group.Ring sulfur atoms may be optionally oxidized to form S-oxides. Ringnitrogen atoms maybe optionally oxidized to form N-oxides. Somenon-limiting examples of 3-8 membered heterocyclyl include azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl,2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, dithianyl,homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, and the like. Some non-limiting examples ofheterocyclyl wherein —CH₂— group is replaced by —C(═O)— moiety are2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl and3,5-dioxopiperidinyl. Some non-limiting examples of heterocyclyl whereinthe ring sulfur atom is oxidized are sulfolanyl,1,1-dioxo-thiomorpholinyl, and the like. The 3-8 membered heterocyclylgroup may be optionally substituted with one or more substituentsdescribed herein.

In another embodiment, heterocyclyl may be a 4-7 membered heterocyclyl,which refers to a monovalent or multivalent, saturated or partiallyunsaturated, non-aromatic monocyclic ring containing 4-7 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen, and of which may, unless otherwise specified, be carbon ornitrogen linked, and of which a —CH₂— group can optionally be replacedby a —C(═O)— group. Ring sulfur atoms may be optionally oxidized to formS-oxides. Ring nitrogen atoms maybe optionally oxidized to formN-oxides. Some non-limiting examples of 4-7 membered heterocyclylinclude azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl,3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl,2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, 1,1-dioxideisothiazolidin-2-yl, pyrrolidin-2-one-1-yl, imidazolidin-2-one-1-yl,oxazolidin-2-one-3-yl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, dioxanyl, thioxanyl, dithianyl, homopiperazinyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl andthiazepinyl. The 4-7 membered heterocyclyl group may be optionallysubstituted with one or more substituents described herein.

The term “heterocyclylene ring” or “heterocyclylene” as usedinterchangeably herein refers to a bivalent saturated or partiallyunsaturated, non-aromatic monocyclic, bicyclic or tricyclic ringcontaining 3-12 ring atoms of which at least one ring atom is selectedfrom nitrogen, sulfur and oxygen, and which may, unless otherwisespecified, be carbon or nitrogen linked, and of which a —CH₂— group canoptionally be replaced by a —C(═O)— group. Ring sulfur atoms may beoptionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. In one embodiment, heterocyclylenering may be a 4-7 membered heterocyclylene ring, which refers to abivalent, saturated or partially unsaturated, non-aromatic monocyclicring containing 4-7 ring atoms, of which at least one ring atom isselected from nitrogen, sulfur and oxygen, and of which may, unlessotherwise specified, be carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides. Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. The 4-7 membered heterocyclylenering may be optionally substituted with one or more substituentsdescribed herein.

In another embodiment, heterocyclylene ring may be a 4-memberedheterocyclylene ring, which refers to a bivalent, saturated or partiallyunsaturated, non-aromatic monocyclic ring containing 4 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen, and of which may, unless otherwise specified, be carbon ornitrogen linked, and of which a —CH₂— group can optionally be replacedby a —C(═O)— group. Ring sulfur atoms may be optionally oxidized to formS-oxides. Ring nitrogen atoms maybe optionally oxidized to formN-oxides. The 4-membered heterocyclylene ring may be optionallysubstituted with one or more substituents described herein.

In another embodiment, heterocyclylene ring may be a 5-memberedheterocyclylene ring, which refers to a bivalent, saturated or partiallyunsaturated, non-aromatic monocyclic ring containing 5 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen, and of which may, unless otherwise specified, be carbon ornitrogen linked, and of which a —CH₂— group can optionally be replacedby a —C(═O)— group. Ring sulfur atoms may be optionally oxidized to formS-oxides. Ring nitrogen atoms maybe optionally oxidized to formN-oxides. The 5-membered heterocyclylene ring may be optionallysubstituted with one or more substituents described herein.

In another embodiment, heterocyclylene ring may be a 6-memberedheterocyclylene ring, which refers to a bivalent, saturated or partiallyunsaturated, non-aromatic monocyclic ring containing 6 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen, and of which may, unless otherwise specified, be carbon ornitrogen linked, and of which a —CH₂— group can optionally be replacedby a —C(═O)— group. Ring sulfur atoms may be optionally oxidized to formS-oxides. Ring nitrogen atoms maybe optionally oxidized to formN-oxides. The 6-membered heterocyclylene ring may be optionallysubstituted with one or more substituents described herein.

In another embodiment, heterocyclylene ring may be a 7-memberedheterocyclylene ring, which refers to a bivalent, saturated or partiallyunsaturated, non-aromatic monocyclic ring containing 7 ring atoms, ofwhich at least one ring atom is selected from nitrogen, sulfur andoxygen, and of which may, unless otherwise specified, be carbon ornitrogen linked, and of which a —CH₂— group can optionally be replacedby a —C(═O)— group. Ring sulfur atoms may be optionally oxidized to formS-oxides. Ring nitrogen atoms maybe optionally oxidized to formN-oxides. The 7-membered heterocyclylene ring may be optionallysubstituted with one or more substituents described herein.

The term “heterocycloalkyl” refers to a monovalent or multivalentsaturated ring having 3 to 12 ring atoms as a monocyclic, bicyclic, ortricyclic ring system in which at least one ring atom is selected fromnitrogen, sulfur and oxygen and which may, unless otherwise specified,be carbon or nitrogen linked, and of which a —CH₂— group can optionallybe replaced by a —C(═O)— group. Ring sulfur atoms may be optionallyoxidized to form S-oxides. Ring nitrogen atoms maybe optionally oxidizedto form N-oxides. Some non-limiting examples of heterocycloalkyl includeazetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl,piperazinyl, morpholinyl, dioxanyl, dithianyl, dithiolanyl,isoxazolidinyl, isothiazolidinyl, 1,2-oxazinanyl, 1,2-thiazinanyl,hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, oxepanyl,thiepanyl, oxazepinyl (e.g. 1,4-oxazepinyl, 1,2-oxazepinyl), diazepinyl(e.g. 1,4-diazepinyl, 1,2-diazepinyl), dioxpinyl (e.g. 1,4-dioxpinyl,1,2-dioxpinyl), thiazepinyl (e.g. 1,4-thiazepinyl, 1,2-thiazepinyl),2-azaspiro[4.4]nonanyl, 1,6-dioxaspiro[4.4]nonanyl,2-azaspiro[4.5]decanyl, 8-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl,3-azaspiro[5.5]undecanyl, 2-azaspiro[5.5]unde canyl,2-octahydro-1H-isoindolyl, octahydrocyclopenta[c]pyrrolyl,hexahydrofuro[3,2-b]furanyl, decahydroisoquinolinyl,hexahydrofuro[2,3-b]furanyl, and the like. The heterocycloalkyl groupmay be optionally substituted with one or more substituents describedherein.

In one embodiment, heterocycloalkyl refers to a 4-7 memberedheterocycloalkyl, which refers to a monovalent or multivalent saturatedheterocyclyl ring containing 4-7 ring atoms, of which at least one ringatom is selected from nitrogen, sulfur and oxygen and which may, unlessotherwise specified, be carbon or nitrogen linked, and of which a —CH₂—group can optionally be replaced by a —C(═O)— group. Ring sulfur atomsmay be optionally oxidized to form S-oxides Ring nitrogen atoms maybeoptionally oxidized to form N-oxides. Some non-limiting examples of 4-7membered heterocycloalkyl include azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,morpholinyl, dioxanyl, dithianyl, dithiolanyl, isoxazolidinyl,isothiazolidinyl, hexahydropyridazinyl, homopiperazinyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, andthiazepinyl. The 4-7 membered heterocycloalkyl group may be optionallysubstituted with one or more substituents described herein.

The term “n membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a 6membered heterocycloalkyl and 1,2,3,4-tetrahydronaphthalenyl is anexample of a 10 membered carbocyclyl group.

The term “unsaturated” refers to a moiety having one or more units ofunsaturation.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur,or phosphorus; the quaternized form of any basic nitrogen; or asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as inN-substituted pyrrolidinyl).

The term “halogen” refers to Fluoro (F), Chloro (Cl), Bromo (Br), orIodo (I).

The term “azido” or “N₃” refers to an azide moiety. This radical may beattached, for example, to a methyl group to form azidomethane (methylazide, MeN3); or attached to a phenyl group to form phenyl azide (PhN₃).

The term “aryl” refers to monocyclic, bicyclic, and tricycliccarbocyclic ring systems having a total of 6 to 14 ring members,preferably, 6 to 12 ring members, and more preferably 6 to 10 ringmembers, wherein at least one ring in the system is aromatic, whereineach ring in the system contains 3 to 7 ring members and that has one ormore points of attachment to the rest of the molecule. The term “aryl”may be used interchangeably with the term “aryl ring” or “aromaticring”. Some non-limiting examples of the aryl group would includephenyl, naphthyl, and anthracenyl. The aryl radical is optionallysubstituted independently with one or more substituents describedherein.

The term “heteroaryl” or “heteroaromatic ring” refers to unsaturated andaromatic monocyclic, bicyclic, and tricyclic ring systems having a totalof 5 to 12 ring members, preferably, 5 to 10 ring members, and morepreferably 5 to 6 ring members, wherein and at least one ring in thesystem contains one or more heteroatoms, wherein each ring in the systemcontains 5 to 7 ring members and that has one or more points ofattachment to the rest of the molecule. The term “heteroaryl” may beused interchangeably with the term “heteroaryl ring” or the term“heteroaromatic ring”. In one embodiment, heteroaryl refers to a 5-12membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independentlyselected from O, S and N. In another embodiment, heteroaryl refers to a5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatomsindependently selected from O, S and N. In another embodiment,heteroaryl refers to a 5-6 membered heteroaryl comprises 1, 2, 3 or 4heteroatoms independently selected from O, S and N. The heteroarylradical is optionally independently substituted with one or moresubstituents described herein.

Some non-limiting examples of the 5-12 membered heteroaryl group includefollowing bicyclyl heteroaryl: benzimidazolyl, benzofuryl,benzothiophenyl, indolyl (e.g., 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl), purinyl, quinolinyl (e.g.,2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g.,1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl), indazolyl (e.g.,3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl),imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-b]pyridazinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl,[1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-c]pyrimidinyl,1H-benzo[d][1,2,3]triazolyl, 3H-imidazo[4,5-b]pyridinyl,1H-pyrrolo[2,3-b]pyridinyl, 1H-benzo[d]imidazolyl,1H-pyrrolo[3,2-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl and[1,2,4]triazolo[1,5-a]pyridinyl, purinyl, and the like. 5-12 memberedheteroaryl group also include 5-6 membered heteroaryl group. Somenon-limiting examples of the 5-6 membered heteroaryl group includefuranyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g.,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl,4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridonyl,pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl),pyrimidonyl, pyrimidinedionyl, pyridazinyl (e.g., 3-pyridazinyl,4-pyridazinyl), pyrazinyl (2-pyrazinyl, 3-pyrazinyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), thienyl (e.g., 2-thienyl,3-thienyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,5-pyrazolyl), pyrazolonyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl,1,3,5-triazinyl, and the like.

The term “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, refers to —CO₂H. The term “carbonyl”,whether used alone or with other terms, such as “aminocarbonyl”, denotes—(C═O)—.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”where amino groups are independently substituted with one alkyl radicalor with two alkyl radicals, respectively. In one embodiment, alkylaminohas one or two alkyl radicals of one to twelve carbon atoms, attached toa nitrogen atom. In another embodiment, alkylamino are “loweralkylamino” radicals having one or two alkyl radicals of one to sixcarbon atoms, attached to a nitrogen atom. In another embodiment,alkylamino are alkylamino radicals having one or two alkyl radicals ofone to four carbon atoms, attached to a nitrogen atom. In still anotherembodiment, alkylamino are alkylamino radicals having one or two alkylradicals of one to three carbon atoms, attached to a nitrogen atom. Somenon-limiting examples of alkylamino include N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-diethylamino, N-ethylpropan-2-amino, and thelike.

The term “arylamino” refers to amino groups, which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “aminoalkyl” refers to linear or branched alkyl radicals havingone to about twelve carbon atoms any one of which may be substitutedwith one or more amino radicals. In one embodiment, the aminoalkyl has1-12 carbon atoms and one or more amino radicals. In another embodiment,the aminoalkyl radicals are “lower aminoalkyl” radicals having 1-6carbon atoms and one or more amino radicals. In another embodiment,aminoalkyl has 1-4 carbon atoms and one or more amino radicals. In stillanother embodiment, aminoalkyl has 1-3 carbon atoms and one or moreamino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl.

As described herein, a bond drawn from a substituent to the center ofone ring within a ring system (as shown below in Structure b) representssubstitution of the substituent at any substitutable position on thering system. For example, as depicted below, Figure b representspossible substitution in any of the positions on the ring D shown inFigure c Structure e.

As described herein, two connecting bonds drawn from the center of onering within a ring system (as shown in Structure i) representsconnection of the connecting bonds attached to the rest of the moleculeat any two substitutable positions on the ring system, and the twoconnecting points (point Q and point Q′) can exchange. For example,Structure i represents possible connection attached to the rest of themolecule in any two of the positions on ring G.

The term “protecting group” or “PG” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxy-carbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and9-fluorenylmethylenoxy-carbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxy-methyl,2-(p-toluenesulfonyl)-ethyl, 2-(p-nitrophenylsulfenyl)-ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term “prodrug” as used herein, represents a compound that istransformed in vivo into a compound of Formula (I). Such atransformation can be affected, for example, by hydrolysis in blood orenzymatic transformation of the prodrug form to the parent form in bloodor tissue. Prodrugs of the compounds disclosed herein may be, forexample, esters. Esters that may be utilized as prodrugs in the presentinvention are phenyl esters, aliphatic (C₁-C₂₄) esters, acyloxymethylesters, carbonates, carbamates, and amino acid esters. For example, acompound disclosed herein that contains an OH group may be acylated atthis position in its prodrug form. Other prodrug forms includephosphates, such as, for example those phosphates resulting from thephosphonation of an OH group on the parent compound. A thoroughdiscussion of prodrugs is provided in Higuchi et al., Pro-drugs as NovelDelivery Systems, Vol. 14, A.C.S. Symposium Series; Roche et al.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987; Rautio et al., Prodrugs: Designand Clinical Applications, Nat. Rev. Drug Discovery, 2008, 7, 255-270,and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med.Chem., 2008, 51, 2328-2345, all of which are incorporated herein byreference.

A “metabolite” refers to a product produced through metabolism in thebody of a specified compound or salt thereof. The metabolites of acompound may be identified using routine techniques known in the art andtheir activities determined using tests such as those described herein.Such products may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds disclosedherein, including compounds produced by a process comprising contactinga compound disclosed herein with a mammal for a period of timesufficient to yield a metabolic product thereof.

A “pharmaceutically acceptable salt” refers to organic or inorganicsalts of a compound disclosed herein. The pharmaceutically acceptablesalts are well known in the art. For example, Berge et al., describepharmaceutically acceptable salts in detail in J. Pharm. Sci., 1977, 66,1-19, which is incorporated herein by reference. Some non-limitingexamples of the pharmaceutically acceptable salt include salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid.

Other examples of the pharmaceutically acceptable salt include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium and N⁺(C₁-C₄ alkyl)₄ salts.This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroil-soluble or dispersible products may be obtained by suchquaternization. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further examples of the pharmaceutically acceptable salt include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, C₁-C₈ sulfonate and aryl sulfonate.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound disclosed herein. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

“Inflammatory disorder/disease” as used herein can refer to any disease,disorder, or syndrome in which an excessive or unregulated inflammatoryresponse leads to excessive inflammatory symptoms, host tissue damage,or loss of tissue function. “Inflammatory disorder/disease” also refersto a pathological state mediated by influx of leukocytes and/orneutrophil chemotaxis.

“Inflammation” as used herein refers to a localized, protective responseelicited by injury or destruction of tissues, which serves to destroy,dilute, or wall off (i.e. sequester) both the injurious agent and theinjured tissue. Inflammation is notably associated with influx ofleukocytes and/or neutrophil chemotaxis. Inflammation can result frominfection with pathogenic organisms and viruses and from noninfectiousmeans such as trauma or reperfusion following myocardial infarction orstroke, immune response to foreign antigen, and autoimmune responses.Accordingly, inflammatory disorders amenable to treatment with thecompounds disclosed herein encompass disorders associated with reactionsof the specific defense system as well as with reactions of thenonspecific defense system.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune diseases,and delayed type hypersensitivity response mediated by T-cells. Chronicinflammatory diseases, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lungand squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, testiculoma, bladder cancer, hepatoma, breastcancer, colon cancer, rectal cancer, colorectal cancer, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, medullary thyroidcarcinoma, melanoma retinoblastoma, hepatic carcinoma, anal carcinoma,penile carcinoma, chronic myelogenous leukemia (CML), acute myeloidleukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocyticleukemia (CLL), as well as head and neck cancer.

Description of Compounds of the Invention

In the present invention, novel compounds which are inhibitors ofprotein kinase activity, in particular JAK kinase, FLT4 kinase, FLT3kinase and Aurora kinase activity, are disclosed. Compounds which areprotein kinase inhibitors may be useful in the treatment of diseasesassociated with inappropriate protein kinase activity, in particularinappropriate JAK, FLT3 FLT4, and Aurora kinases activity, for examplein the treatment and prevention of diseases mediated by JAK kinase, FLT4kinase, FLT3 kinase and Aurora kinases involved signalling pathways.Such diseases include proliferative disease, autoimmune disease,allergic disease, inflammatory disease, transplantation rejection, andtheir co-morbidities. In particular, a compound of the present inventionmay be useful in the treatment of diseases such as cancer (e.g.colorectal cancer, hodgkin lymphoma, non-hodgkin lymphoma, gastriccancer, esophageal cancer, breast cancer, lung cancer, hepaticcarcinoma, prostate cancer, pancreatic cancer, thyroid cancer, bladdercancer, kidney cancer, brain tumor, cancer of the head and neck, cancerof the CNS, malignant glioma, non-small cell lung cancer, cervicalcancer, testicular cancer, multiple myeloma, lymphoma, malignantlymphoma, small cell lung cancer, neuroblastoma, neuroendocrine tumor,medullary thyroid carcinoma, melanoma, retinoblastoma, metrocarcinoma,ovarian cancer, chronic myelogenous leukemia (CML), acute myeloidleukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocyticleukemia (CLL)), primary gigantic globulin hematic disease, mononuclearcell leukemia, sezary syndrome, infectious mononucleosis, colitis,pancreatitis, atherosclerosis, pulmonary fibrosis, polycythemia vera,essential thrombocytosis, myelofibrosis, chronic obstruction pulmonarydisease (COPD), asthma, systemic and cutaneous lupus erythematosis,lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type Idiabetes mellitus, allergic airway disease, sinusitis, eczema, hives,food allergies, allergies to insect venom, inflammatory bowel syndrome,Crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriaticarthritis, organ transplant rejection, tissue transplant rejection, celltransplant rejection, to name a few.

In one embodiment, the compounds disclosed herein may show potentinhibitory activities against one or more protein kinases.

Specifically, in one aspect, provided herein is a compound havingFormula (I):

or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug thereof, wherein each ofW, A, T, Z and R¹ is as defined herein.

In one embodiment, W is a 4-7 membered saturated monocyclicheterocyclylene or saturated monocyclic C₅-C₇carbocyclylene, wherein Wis optionally substituted by 1, 2, 3, 4 or 5 R² groups;

T is C₆-C₁₂ aryl or 5-12 membered heteroaryl, wherein T is optionallysubstituted by 1, 2, 3, 4 or 5 R³ groups;

A is an optionally substituted 9-membered heteroaryl group, havingFormula (A-1), (A-2), (A-3), (A-4), (A-5) or (A-6):

wherein each V₁ and V₂ is independently CR⁴ or N;

each U₁, U₂ and U₃ is independently CR⁴ or N;

each of U₄ and U₆ is independently CR⁴, N, NR⁵, O or S;

U₅ is independently CR⁴, O or S;

wherein at least one of V₁, V₂, U₃, U₄, U₅ and U₆ is not CR⁴; Z is H,C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl or 3-12 membered heterocyclyl, whereineach of the C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyland 3-12 memberedheterocyclylis optionally substituted by 1, 2, 3, 4 or 5 R⁹ groups;

R¹ is H, F, Cl, Br, I, NO₂, N₃, CN, C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl,C₃-C₁₂ cycloalkyl or 3-12 membered heterocyclyl, wherein each of theC₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₃-C₁₂ cycloalkyl and 3-12 memberedheterocyclyl is optionally substituted by 1, 2 or 3 R⁹ groups;

each R² and R³ is independently F, Cl, Br, I, NO₂, N₃, CN, OH, C₁-C₁₂alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl,5-12 membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl),—(C₁-C₄ alkylene)-(5-12 membered heteroaryl), —(CR⁶R⁷)_(n)—OR^(c),—(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)C(═O)R⁸, —(CR⁶R⁷)_(n)OC(═O)R⁸,—O(CR⁶R⁷)_(n)—R^(c), —(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸,—(CR⁶R⁷)_(n)C(═O)OR^(c), —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b),—N(R^(c))C(═O)NR^(a)R^(b), —N(R^(c))S(═O)_(m)NR^(a)R^(b),—C(═O)N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n)S(═O)_(m)R⁸, —N(R^(c))S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₁₂ alkyl,C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl)and —(C₁-C₄ alkylene)-(5-12 membered heteroaryl) is optionallyindependently substituted by 1, 2, 3, 4 or 5 R⁹ groups;

each R⁴ is independently H, F, Cl, Br, I, NO₂, N₃, CN, C₁-C₁₂ alkyl,C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)C(═O)R⁸, —(CR⁶R⁷)_(n)OC(═O)R⁸, —O(CR⁶R⁷)_(n)—R^(c),—(CR⁶R⁷)_(n)—N(R^(c))C═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —N(R^(c))C═O)NR^(a)R^(b),—N(R^(c))S(═O)_(m)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸,—N(R^(c))S(═O)_(m)R⁸ or —(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), or twoadjacent R⁴ taken together with the carbon atoms to which they areattached form a C₃-C₁₂ carbocycle or 3-12 membered heterocycle, whereineach of the C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12membered heterocyclyl, 5-12 membered heteroaryl, C₃-C₁₂ carbocycle and3-12 membered heterocycle is optionally independently substituted by 1,2, 3, 4 or 5 R⁹ groups;

each R⁵ is independently absent, or H, C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl,C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl,C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl,—(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)C(═O)R⁸,—(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₁₂ alkyl,C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl and 5-12membered heteroaryl is optionally independently substituted by 1, 2 or 3R⁹ groups;

each R⁶ and R⁷ is independently H, F, Cl, Br, I, NO₂, N₃, CN, C₁-C₁₂alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl or 5-12 memberedheteroaryl, or R⁶ and R⁷ taken together with the carbon atom to whichthey are attached form a C₃-C₁₂ carbocycle or 3-12 membered heterocycle,wherein each of the C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 memberedheterocyclyl, 5-12 membered heteroaryl, C₃-C₁₂ carbocycle and 3-12membered heterocycle is optionally independently substituted by 1, 2 or3 R⁹ groups;

each R⁸ is independently C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 memberedheterocyclyl, 5-12 membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂cycloalkyl), —(C₁-C₄ alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄alkylene)-(C₆-C₁₂ aryl) or —(C₁-C₄ alkylene)-(5-12 membered heteroaryl),wherein each R⁸ is optionally substituted by 1, 2 or 3 R⁹ groups;

each R⁹ is independently F, Cl, Br, I, CN, NO₂, N₃, —OH, —NH₂, C₁-C₁₂alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12 memberedheteroaryl, —NH(C₁-C₁₂ alkyl), —NH(CH₂)_(n)—(C₃-C₁₂ cycloalkyl),—NH(CH₂)_(n)—(C₆-C₁₂ aryl), —NH(CH₂)_(n)-(3-12 membered heterocyclyl),—NH(CH₂)_(n)-(5-12 membered heteroaryl), —N(C₁-C₁₂ alkyl)₂,—N[(CH₂)_(n)—(C₃-C₁₂ cycloalkyl)]₂, —N[(CH₂)_(n)—(C₆-C₁₂ aryl)]₂,—N[(CH₂)_(n)-(3-12 membered heterocyclyl)]₂, —N[(CH₂)_(n)-(5-12 memberedheteroaryl)]₂, —O(C₁-C₁₂ alkyl), —O(CH₂)_(n)—(C₃-C₁₂cycloalkyl),—O(CH₂)_(n)—(C₆-C₁₂ aryl), —O(CH₂)_(n)-(3-12 membered heterocyclyl) or—O(CH₂)_(n)-(5-12 membered heteroaryl);

each R^(a), R^(b) and R^(c) is independently H, C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, —(C₁-C₄alkylene)-(C₃-C₆ cycloalkyl), 4-7 membered heterocyclyl, —(C₁-C₄alkylene)-(4-7 membered heterocyclyl), C₆-C₁₂ aryl, —(C₁-C₄alkylene)-(C₆-C₁₂ aryl), 5-12 membered heteroaryl or —(C₁-C₄alkylene)-(5-12 membered heteroaryl), or R^(a) and R^(b) taken togetherwith the nitrogen atom to which they are attached form a 4-7 memberedheterocycle, wherein each of the C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, —(C₁-C₄ alkylene)-(C₃-C₆cycloalkyl), 4-7 membered heterocyclyl, —(C₁-C₄ alkylene)-(4-7 memberedheterocyclyl), C₆-C₁₂ aryl, —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl), 5-12membered heteroaryl, —(C₁-C₄ alkylene)-(5-12 membered heteroaryl) and4-7 membered heterocycle is optionally independently substituted by 1,2, 3 or 4 substitutents independently selected from F, Cl, Br, CN, N₃,—OH, —NH₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆alkylamino;

each n is independently 0, 1, 2, 3 or 4; and

each m is independently 1 or 2.

In another embodiment, W is a saturated monocyclic heterocyclylenederived from one of the following heterocyclic compounds:

and wherein W is optionally substituted by 1, 2 or 3 R² groups.

In one embodiment, W is:

and wherein W is optionally substituted by 1, 2 or 3 R² groups.

In another embodiment, T is phenyl or 5-6 membered heteroaryl, wherein Tis optionally substituted by 1, 2, 3 or 4 R³ groups.

In one embodiment, T is phenyl, pyridyl, pyridonyl, pyrimidinyl,pyrimidonyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, thiazolyl,isothiazolyl, tetrazolyl, triazolyl, thienyl, pyrazolyl, oxadiazolyl,thiadiazolyl or triazinyl, wherein T is optionally substituted by 1, 2or 3 R³ groups.

In another embodiment, A is:

wherein each CH atom in A is optionally independently substituted by aR⁴ group; each NH in A is optionally independently substituted by a R⁵group.

In one embodiment, Z is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl or 4-7 memberedheterocyclyl, wherein each of the C₁-C₆ alkyl, C₃-C₆ cycloalkyl and 4-7membered heterocyclyl is optionally substituted by 1, 2 or 3 R⁹ groups.

In another embodiment, Z is H, methyl, ethyl, n-propyl, i-propyl,cyclopropyl or cyclobutyl.

In one embodiment, R¹ is H, F, Cl, Br, NO₂, N₃, CN, C₁-C₄ alkyl, C₁-C₄heteroalkyl, C₃-C₆ cycloalkyl or 4-7 membered heterocyclyl, wherein eachof the C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₃-C₆ cycloalkyl and 4-7 memberedheterocyclyl is optionally substituted by 1, 2 or 3 R⁹ groups.

In another embodiment, each R² and R³ is independently F, Cl, Br, NO₂,N₃, CN, OH, C₁-C₄ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 memberedheterocyclyl, 5-6 membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c),—(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)OC(═O)R⁸,—(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸,—N(R^(c))S(═O)_(m)R⁸ or —(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein eachof the C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 memberedheterocyclyl and 5-6 membered heteroaryl is optionally independentlysubstituted by 1, 2 or 3 R⁹ groups.

In one embodiment, R¹ is H, F, Cl, Br, NO₂, N₃, CN, C₁-C₄ alkyl, C₁-C₄heteroalkyl, C₃-C₆ cycloalkyl or 4-7 membered heterocyclyl, wherein eachof the C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₃-C₆ cycloalkyl and 4-7 memberedheterocyclyl is optionally substituted by 1, 2 or 3 R⁹ groups;

each R² and R³ is independently F, Cl, Br, NO₂, N₃, CN, OH, C₁-C₄ alkyl,C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 memberedheteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)—N(R^(c))C═O)R⁸,—(CR⁶R⁷)_(n)C(═O)OR^(c), —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b),—(CR⁶R⁷)_(n)S(═O)_(m)R⁸, N(R^(c))S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl and 5-6 memberedheteroaryl is optionally independently substituted by 1, 2 or 3 R⁹groups.

In one embodiment, each R⁴ is independently H, F, Cl, Br, NO₂, N₃, CN,C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)—N(R^(c))C═O)R⁸,—(CR⁶R⁷)_(n)C(═O)OR^(c), —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b),—(CR⁶R⁷)_(n)S(═O)_(m)R⁸, —N(R^(c))S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), or two adjacent R⁴ taken together withthe carbon atoms to which they are attached form a C₃-C₆ carbocycle or4-7 membered heterocycle, wherein each of the C₁-C₆ alkyl,C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 memberedheteroaryl, C₃-C₆ carbocycle and 4-7 membered heterocycle is optionallyindependently substituted by 1, 2 or 3 R⁹ groups.

In another embodiment, each R⁴ is independently H, F, Cl, Br, N₃, CN,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃,—CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,—(CR⁶R⁷)_(n)C(═O)OR^(c) or —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), or two adjacentR⁴ taken together with the carbon atoms to which they are attached forma C₄-C₆ carbocycle or 4-7 membered heterocycle, wherein each of themethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃,—CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₄-C₆ carbocycleand 4-7 membered heterocycle is optionally independently substituted by1, 2 or 3 R⁹ groups.

In one embodiment, each R⁵ is independently absent, or H, C₁-C₆ alkyl,C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 memberedheteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl and 5-6 memberedheteroaryl is optionally independently substituted by 1, 2 or 3 R⁹groups.

In another embodiment, each R⁵ is independently absent, or H, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,—CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃, —CH₂C(CH₃)₂OH,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl,pyrrolidinyl, morpholinyl, piperazinyl, —(CR⁶R⁷)_(n)C(═O)OR^(c) or—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), wherein each of the methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —CH₂OH, —CH₂CH₂OH,—CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃, —CH₂C(CH₃)₂OH, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl,morpholinyl and piperazinyl is optionally independently substituted by1, 2 or 3 R⁹ groups.

In one embodiment, each R⁶ and R⁷ is independently H, F, Cl, Br, CN,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl or 5-6 memberedheteroaryl, or R⁶ and R⁷ taken together with the carbon atom to whichthey are attached form a C₃-C₆ carbocycle or 4-7 membered heterocycle,wherein each of the C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6membered heteroaryl, C₃-C₆ carbocycle and 4-7 membered heterocycle isoptionally independently substituted by 1, 2 or 3 R⁹ groups.

In another embodiment, each R⁸ is independently C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7membered heterocyclyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆cycloalkyl), —(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃alkylene)-phenyl or —(C₁-C₃ alkylene)-(5-6 membered heteroaryl), whereineach R⁸ is optionally substituted by 1, 2 or 3 R⁹ groups.

In one embodiment, each R⁹ is independently F, Cl, Br, CN, N₃, —NH₂,—OH, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl,—NH(C₁-C₆ alkyl), —NH(CH₂)_(n)—(C₃-C₆ cycloalkyl), —NH(CH₂)_(n)-phenyl,—NH(CH₂)_(n)-(4-7 membered heterocyclyl), —NH(CH₂)_(n)-(5-6 memberedheteroaryl), —N(C₁-C₆ alkyl)₂, —N[(CH₂)_(n)—(C₃-C₆ cycloalkyl)]₂,—N[(CH₂)_(n)-phenyl]₂, —N[(CH₂)_(n)-(4-7 membered heterocyclyl)]₂,—N[(CH₂)_(n)-(5-6 membered heteroaryl)]₂, —O(C₁-C₆ alkyl),—O(CH₂)_(n)—(C₃-C₆ cycloalkyl), —O(CH₂)_(n)-phenyl, —O(CH₂)_(n)-(4-7membered heterocyclyl) or —O(CH₂)_(n)-(5-6 membered heteroaryl).

In another embodiment, each R^(a), R^(b) and R^(c) is independently H,methyl, ethyl, n-propyl, isopropyl, n-butyl, C₁-C₄ heteroalkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl,—(C₁-C₂ alkylene)-(C₃-C₆ cycloalkyl), —(C₁-C₂ alkylene)-(4-7 memberedheterocyclyl), —(C₁-C₂ alkylene)-phenyl or —(C₁-C₂ alkylene)-(5-6membered heteroaryl), or R^(a) and R^(b) taken together with thenitrogen atom to which they are attached form azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl, wherein each of the methyl, ethyl, n-propyl,isopropyl, n-butyl, C₁-C₄ heteroalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C₁-C₂alkylene)-(C₃-C₆ cycloalkyl), 4-6 membered heterocyclyl, —(C₁-C₂alkylene)-(4-7 membered heterocyclyl), phenyl, —(C₁-C₂ alkylene)-phenyl,5-6 membered heteroaryl, —(C₁-C₂ alkylene)-(5-6 membered heteroaryl),azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl is optionallyindependently substituted by 1, 2 or 3 substitutents independentlyselected from F, Cl, CN, N₃, —OH, —NH₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy and C₁-C₄ alkylamino.

In yet another embodiment, some non-limiting examples of the compounddisclosed herein, and their stereoisomer, tautomer, N-oxide, solvate,pharmaceutically acceptable salts and solvates thereof, are shown in thefollowing:

TABLE 1

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

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Unless otherwise stated, all stereoisomers, tautomers, solvates,metabolites, salts, and pharmaceutically acceptable prodrugs of thecompounds of Formula (I) are within the scope of the invention.

The compounds disclosed herein may contain asymmetric or chiral centers,and therefore exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of compounds of Formula (I), including butnot limited to, diastereomers, enantiomers, atropisomers, conformers(rotamers) and geometric (cis/trans) isomers as well as mixtures thereofsuch as racemic mixtures, form part of the present invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of Formula (I) may exist in different tautomeric forms,and all such forms are embraced within the scope of the invention, asdefined by the claims.

The compounds of Formula (I) can be in the form of salts. In oneembodiment, the salts are pharmaceutically acceptable salts. The phrase“pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith. In another embodiment, the salts are not necessarilypharmaceutically acceptable salts, and which may be useful asintermediates for preparing and/or purifying compounds of Formula (I)and/or for separating enantiomers of compounds of Formula (I).

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, subsalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts. Organic bases from which salts can be derivedinclude, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like. Certain organicamines include isopropylamine, benzathine, cholinate, diethanolamine,diethylamine, lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Furthermore, the compounds disclosed herein, including their salts, canalso be obtained in the form of their hydrates, or include othersolvents such as ethanol, DMSO, and the like, used for theircrystallization. The compounds of the present invention may inherentlyor by design form solvates with pharmaceutically acceptable solvents(including water); therefore, it is intended that the invention embraceboth solvated and unsolvated forms.

Any formula given herein is also intended to represent isotopicallyunenriched forms as well as isotopically enriched forms of thecompounds. Isotopically enriched compounds have structures depicted bythe formulas given herein except that one or more atoms are replaced byan atom having a selected atomic mass or mass number. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine, and chlorine, such as ²H (deuterium, D), ³H, ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I, respectively.

In another aspect, the compounds of the invention include isotopicallyenriched compounds as defined herein, for example those into whichradioactive isotopes, such as ³H, ¹⁴C and ¹⁸F, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically enriched compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F-enriched compound may be particularlydesirable for PET or SPECT studies. Isotopically-enriched compounds ofFormula (I) can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of Formula (I). The concentration of such aheavier isotope, specifically deuterium, may be defined by the isotopicenrichment factor. The term “isotopic enrichment factor” as used hereinmeans the ratio between the isotopic abundance and the natural abundanceof a specified isotope. If a substituent in a compound of this inventionis denoted deuterium, such compound has an isotopic enrichment factorfor each designated deuterium atom of at least 3500 (52.5% deuteriumincorporation at each designated deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium incorporation), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation). Pharmaceuticallyacceptable solvates in accordance with the invention include thosewherein the solvent of crystallization may be isotopically substituted,e.g. D₂O, acetone-d₆, DMSO-d₆.

In another aspect, provided herein are intermediates for preparing thecompounds disclosed herein.

In another aspect, provided herein are methods of preparing, methods ofseparating, and methods of purifying the compounds disclosed herein.

In another aspect, provided herein is a pharmaceutical compositioncomprising a therapeutically effective amount of the compound disclosedherein, and a pharmaceutically acceptable excipient, carrier, adjuvant,vehicle or a combination thereof. In some embodiments, the compositionis a liquid, solid, semi-solid, gel, or an aerosol form.

In another aspect, provided herein is a method of treating a disease ordisorder modulated by one or more protein kinases such as JAK kinases,FLT4 kinase, FLT3 kinase and Aurora kinases, comprising administering toa mammal in need of such treatment an effective amount of a compound ora pharmaceutical composition disclosed herein. In one embodiment, thedisease or disorder is selected from proliferative disease, autoimmunedisease, allergic disease, inflammatory disease, transplantationrejection or cancer.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment of disease ordisorder selected from proliferative disease, autoimmune disease,allergic disease, inflammatory disease, transplantation rejection orcancer.

In another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment of disease or disorder selected fromproliferative disease, autoimmune disease, allergic disease,inflammatory disease, transplantation rejection or cancer.

In still another aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for modulating the activity of protein kinase, wherein theprotein kinase is JAK1 kinase, JAK2 kinase, JAK3 kinase, TYK2 kinase,Aurora-A kinase, Aurora-B kinase, FLT4 kinase, FLT3 kinase or acombination thereof; especically JAK kinases, such as JAK1 kinase and/orJAK2 kinase. PHARMACEUTICAL COMPOSITION, FORMULATIONS AND ADMINISIRATION OF THE COMPOUNDS OF THE INVENTION

The present invention provides a pharmaceutical composition that includea compound disclosed herein, or a compound listed in Table 1; and apharmaceutically acceptable excipient, carrier, adjuvant, vehicle or acombination thereof. The amount of compound in the pharmaceuticalcomposition disclosed herein is such that is effective to detectablyinhibit a protein kinase in a biological sample or in a patient.

It will also be appreciated that certain compounds disclosed herein canexist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. Some non-limitingexamples of pharmaceutically acceptable derivative includepharmaceutically acceptable prodrugs, salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to apatient in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

The pharmaceutical compositions disclosed herein may be prepared andpackaged in bulk form wherein a safe and effective amount of thecompound disclosed herein can be extracted and then given to the patientsuch as with powders or syrups. Alternatively, the pharmaceuticalcompositions disclosed herein may be prepared and packaged in unitdosage form wherein each physically discrete unit contains the compounddisclosed herein. When prepared in unit dosage form, the pharmaceuticalcompositions of the invention typically may contain, for example, from0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of thecompound disclosed herein.

As used herein, “pharmaceutically acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled such that interactions whichwould substantially reduce the efficacy of the compound disclosed hereinwhen administered to a patient and interactions which would result inpharmaceutical compositions that are not pharmaceutically acceptable areavoided. In addition, each excipient must bepharmaceutically-acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting of the compound or compoundsdisclosed herein once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients comprise the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweetners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what other excipientsare present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005,ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, andEncyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C.Boylan, 1988-1999, Marcel Dekker, New York, the contents of each ofwhich is incorporated by reference herein, are disclosed variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds disclosedherein, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

The pharmaceutical compositions disclosed herein are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Accordingly, in another aspect the invention is directed to process forthe preparation of a pharmaceutical composition comprising the compounddisclosed herein and a pharmaceutically acceptable excipient, carrier,adjuvant, vehicle or a combination thereof, which comprises mixing theingredients. A pharmaceutical composition comprising the compounddisclosed herein may be prepared by, for example, admixture at ambienttemperature and atmospheric pressure.

The compounds disclosed herein will typically be formulated into adosage form adapted for administration to the patient by the desiredroute of administration. For example, dosage forms include those adaptedfor (1) oral administration such as tablets, capsules, caplets, pills,troches, powders, syrups, elixirs, suspensions, solutions, emulsions,granula, and cachets; (2) parenteral administration such as sterilesolutions, suspensions, and freeze drying powder; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols, solutions, anddry powders; and (6) topical administration such as creams, ointments,lotions, solutions, pastes, sprays, foams, and gels.

In one embodiment, the compounds disclosed herein will be formulated fororal administration. In another embodiment, the compounds disclosedherein will be formulated for inhaled administration. In a furtherembodiment, the compounds disclosed herein will be formulated forintranasal administration. In another embodiment, the compoundsdisclosed herein will be formulated for transdermal administration. In afurther embodiment, the compounds disclosed herein will be formulatedfor topical administration.

The pharmaceutical compositions provided herein can be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenyl salicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein can be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions provided herein can be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable nonaqueous liquid or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein can be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The compounds disclosed herein may also be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, orpolyethyleneoxidepolylysine substituted with palmitoyl residues.Furthermore, the compounds disclosed herein may be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates and cross-linked or amphipathic block copolymers ofhydrogels.

The pharmaceutical compositions provided herein can be formulated asimmediate or modified release dosage forms, including delayed-,sustained-, pulsed-, controlled-, targeted-, and programmed-releaseforms.

The pharmaceutical compositions provided herein can be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction.

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfate and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, andsulfobutylether 7-P-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein can be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampoule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein can be formulated asimmediate or modified release dosage forms, including delayed-,sustained-, pulsed-, controlled-, targeted-, and programmed-releaseforms.

The pharmaceutical compositions can be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

In another aspect, The pharmaceutical compositions disclosed herein canbe formulated in any dosage forms that are adapted for administration toa patient by inhalation, for example as a dry powder, an aerosol, asuspension, or a solution composition. In one embodiment, thepharmaceutical compositions disclosed herein can be formulated in adosage form adapted for administration to a patient by inhalation as adry powder. In a further embodiment, the pharmaceutical compositionsdisclosed herein can be formulated in a dosage form adapted foradministration to a patient by inhalation via a nebulizer. Dry powdercompositions for delivery to the lung by inhalation typically comprisethe compounds disclosed herein as a finely divided powder together withone or more pharmaceutically-acceptable excipients as finely dividedpowders. Pharmaceutically-acceptable excipients particularly suited foruse in dry powders are known to those skilled in the art and includelactose, starch, mannitol, and mono-, di-, and polysaccharides. Thefinely divided powder may be prepared by, for example, micronisation andmilling. Generally, the size-reduced (eg micronised) compound can bedefined by a D50 value of about 1 to about 10 microns (for example asmeasured using laser diffraction).

Aerosols may be formed by suspending or dissolving the compounddisclosed herein in a liquified propellant. Suitable propellants includehalocarbons, hydrocarbons, and other liquified gases. Representativepropellants include: trichlorofluoromethane (propellant 11),dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane(propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane(HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12),heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane,perfluoropentane, butane, isobutane, and pentane. Aerosols comprisingthe compound disclosed herein will typically be administered to apatient via a metered dose inhaler (MDI). Such devices are known tothose skilled in the art.

The aerosol may contain additional pharmaceutically-acceptableexcipients typically used with MDIs such as surfactants, lubricants,cosolvents and other excipients to improve the physical stability of theformulation, to improve valve performance, to improve solubility, or toimprove taste.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the patient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 1986,3(6), 318.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils. Ointments, creams andgels, may, for example, be formulated with an aqueous or oily base withthe addition of suitable thickening and/or gelling agent and/orsolvents. Such bases may thus, for example, include water and/or oilsuch as liquid paraffin or a vegetable oil such as arachis oil or castoroil, or a solvent such as polyethylene glycol. Thickening agents andgelling agents which may be used according to the nature of the baseinclude soft paraffin, aluminium stearate, cetostearyl alcohol,polyethylene glycols, woolfat, beeswax, carboxypolymethylene andcellulose derivatives, and/or glyceryl monostearate and/or non-ionicemulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or nonaqueous base also comprising one ormore dispersing agents, solubilizing agents, suspending agents orpreservatives.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions may be applied as a topical ointment orcream. When formulated in an ointment, the compound disclosed herein maybe employed with either a paraffinic or a water-miscible ointment base.Alternatively, the compound disclosed herein may be formulated in acream with an oil-in-water cream base or a water-in-oil base.

Use of the Compounds and Compositions of the Invention

The present invention provides a method of using a compound disclosedherein, or a pharmaceutical composition comprising the compounddisclosed herein for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected via one ormore protein kinases activity, such as JAK kinases (including JAK1,JAK2, JAK3 or TYK2 kinase), FLT4 kinase, FLT3 kinase, and Aurora kinases(including Aurora-A, Aurora-B and Aurora-C) activity or one or moresymptoms of diseases or disorders that are mediated or otherwiseaffected via one or more protein kinases activity, such as JAK kinases(including JAK1, JAK2, JAK3 or TYK2 kinase), FLT4 kinase, FLT3 kinaseand Aurora kinases (including Aurora-A, Aurora-B and Aurora-C kinase)activity.

JAK kinases can be wild type and/or mutant form of JAK1, JAK2, JAK3 orTYK2 kinase.

In one embodiment, provided herein is a method of using a compounddisclosed herein or a pharmaceutical composition comprising a compounddisclosed herein for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected viainappropriate JAK1 kinase activity or one or more symptoms of diseasesor disorders that are mediated or otherwise affected via inappropriateJAK1 kinase activity. In another embodiment, a disease, a disorder orone or more symptoms of diseases or disorders is related to theinappropriate activity of JAK2 kinase. In yet another embodiment, adisease, a disorder or one or more symptoms of diseases or disorders isrelated to the inappropriate activity of JAK3 kinase.

In one embodiment, provided herein is a method of using a compounddisclosed herein or a pharmaceutical composition comprising a compounddisclosed herein for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected viainappropriate FLT3 kinase activity or one or more symptoms of diseasesor disorders that are mediated or otherwise affected via inappropriateFLT3 kinase activity.

In one embodiment, provided herein is a method of using a compounddisclosed herein or a pharmaceutical composition comprising a compounddisclosed herein for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected viainappropriate FLT4 kinase activity or one or more symptoms of diseasesor disorders that are mediated or otherwise affected via inappropriateFLT4 kinase activity. In one embodiment, provided herein is a method ofusing a compound disclosed herein or a pharmaceutical compositioncomprising a compound disclosed herein for the treatment, prevention, oramelioration of a disease or disorder that is mediated or otherwiseaffected via inappropriate Aurora-A kinase activity or one or moresymptoms of diseases or disorders that are mediated or otherwiseaffected via inappropriate Aurora-A kinase activity. In anotherembodiment, a disease, a disorder or one or more symptoms of diseases ordisorders is related to the inappropriate activity of Aurora-B kinase.In yet another embodiment, a disease, a disorder or one or more symptomsof diseases or disorders is related to the inappropriate activity ofAurora-C kinase.

“Inappropriate JAK kinase activity” refers to any JAK kinase activitythat deviates from the normal JAK kinase activity expected in aparticular patient. Inappropriate JAK kinase may take the form of, forinstance, an abnormal increase in activity, or an aberration in thetiming and or control of JAK kinase activity. Such inappropriateactivity may result then, for example, from overexpression or mutationof the protein kinase leading to inappropriate or uncontrolledactivation. Accordingly, in another aspect the invention is directed tomethods of treating such diseases and disorders.

Consistent with the description above, such diseases or disordersinclude without limitation: myeloproliferative disorders such as primarygigantic globulin hematic disease, mononuclear cell leukemia, sezarysyndrome, infectious mononucleosis, colitis, pancreatitis,atherosclerosis, pulmonary fibrosis, polycythemia vera (PCV), essentialthrombocythemia and idiopathic myelofibrosis (IMF); leukemia such asmyeloid leukemia including chronic myeloid leukemia (CML),imatinib-resistant forms of CML, acute myeloid leukemia (AML), and asubtype of AML, acute megakaryoblastic leukemia (AMKL);lymphoproliferative diseases such as acute lymphocytic leukemia (ALL)and myeloma; cancer including colorectal cancer, hodgkin lymphoma,non-hodgkin lymphoma, gastric cancer, esophageal cancer, breast cancer,lung cancer, hepatic carcinoma, prostate cancer, pancreatic cancer,thyroid cancer, bladder cancer, kidney cancer, brain tumor, cancer ofthe head and neck, cancer of the CNS, malignant glioma, non-small celllung cancer, cervical cancer, testicular cancer, multiple myeloma,lymphoma, malignant lymphoma, small cell lung cancer, neuroblastoma,neuroendocrine tumor, medullary thyroid carcinoma, melanoma,retinoblastoma, metrocarcinoma and ovarian cancer, and allergic orinflammatory diseases or disorders related to immune dysfunction,immunodeficiency, immunomodulation, autoimmune diseases, transplantationrejection, graft-versus-host disease, wound healing, kidney disease,multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis,psoriasis, allergic rhinitis, inflammatory bowel disease includingCrohn's disease and ulcerative colitis (UC), systemic lupuserythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis,osteoporosis, asthma and chronic obstructive pulmonary disease (COPD)and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

In one aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for preventing and/or treatingproliferative disease, autoimmune disease, allergic disease,inflammatory disease, transplantation rejection or cancer in mammalsincluding humans. In yet another aspect, provided herein is a method oftreating a mammal having, or at risk of having a disease or disclosedherein, said method comprising administering an effectivecondition-treating or condition-preventing amount of one or more of thepharmaceutical compositions or the compounds disclosed herein. In aparticular aspect, provided here is a method of treating a mammalhaving, or at risk of having proliferative disease, autoimmune disease,allergic disease, inflammatory disease, transplantation rejection orcancer.

In additional method of treatment aspects, provided herein is a methodof treatment and/or prophylaxis of a mammal susceptible to or afflictedwith a proliferative disease, said methods comprising administering aneffective condition-treating or condition-preventing amount of one ormore of the pharmaceutical compositions or compounds disclosed herein.In a specific embodiment, the proliferative disease is selected fromcancer (e.g. solid tumors such as uterine leiomyosarcoma or prostatecancer), polycythemia vera, essential thrombocytosis, myelofibrosis,leukemia (e.g. AML, CML, ALL or CLL), and multiple myeloma.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of a proliferative disease. In a specific embodiment, theproliferative disease is selected from cancer (e.g. solid tumors such asuterine leiomyosarcoma or prostate cancer), polycythemia vera, essentialthrombocytosis, myelofibrosis, leukemia (e.g. AML, CML, ALL or CLL), andmultiple myeloma.

In yet another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein for use in the manufactureof a medicament for the treatment, and/or prophylaxis of a proliferativedisease. In a specific embodiment, the proliferative disease is selectedfrom cancer (e.g. solid tumors such as uterine leiomyosarcoma orprostate cancer), polycythemia vera, essential thrombocytosis,myelofibrosis, leukemia (e.g. AML, CML, ALL or CLL), and multiplemyeloma.

In another aspect, provided herein is a method of treatment and/orprophylaxis of a mammal susceptible to or afflicted with an autoimmunedisease. The methods comprise administering an effectivecondition-treating or condition-preventing amount of one or more of thepharmaceutical compositions or compounds disclosed herein. In a specificembodiment, the autoimmune disease is selected from COPD, asthma,systemic and cutaneous lupus erythematosis, lupus nephritis,dermatomyositis, Sjogren's syndrome, psoriasis and type I diabetesmellitus.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of an autoimmune disease. In a specific embodiment, theautoimmune disease is selected from COPD, asthma, systemic and cutaneouslupus erythematosis, lupus nephritis, dermatomyositis, Sjogren'ssyndrome, psoriasis and type I diabetes mellitus.

In yet another aspect, provided here is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment, and/or prophylaxis of an autoimmunedisease. In a specific embodiment, the autoimmune disease is selectedfrom COPD, asthma, systemic and cutaneous lupus erythematosis, lupusnephritis, dermatomyositis, Sjogren's syndrome, psoriasis and type Idiabetes mellitus.

In a method of treatment aspects, provided herein are methods oftreatment and/or prophylaxis of a mammal susceptible to or afflictedwith an allergic disease. The methods comprising administering aneffective condition-treating or condition-preventing amount of one ormore of the pharmaceutical compositions or the compounds disclosedherein. In a specific embodiment, the allergic disease is selected fromallergic airway disease, sinusitis, eczema and hives, food allergies andallergies to insect venom.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of an allergic disease. In a specific embodiment, theallergic disease is selected from allergic airway disease, sinusitis,eczema and hives, food allergies and allergies to insect venom.

In yet another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment, or prophylaxis of an allergic disease. Ina specific embodiment, the allergic disease is selected from allergicairway disease, sinusitis, eczema and hives, food allergies andallergies to insect venom.

In another aspect, provided herein are methods of treatment and/orprophylaxis of a mammal susceptible to or afflicted with an inflammatorydisease. The methods comprise administering an effectivecondition-treating or condition-preventing amount of one or more of thepharmaceutical compositions or the compounds disclosed herein. In aspecific embodiment, the inflammatory disease is selected frominflammatory bowel syndrome, Crohn's disease, rheumatoid arthritis,juvenile arthritis and psoriatic arthritis.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of an inflammatory disease. In a specific embodiment, theinflammatory disease is selected from inflammatory bowel syndrome,Crohn's disease, rheumatoid arthritis, juvenile arthritis and psoriaticarthritis. In yet another aspect, provided herein is the use of thecompound or the pharmaceutical composition disclosed herein in themanufacture of a medicament for the treatment, and/or prophylaxis of aninflammatory disease. In a specific embodiment, the inflammatory diseaseis selected from inflammatory bowel syndrome, Crohn's disease,rheumatoid arthritis, juvenile arthritis and psoriatic arthritis.

In another aspect, provided herein are methods of treatment and/orprophylaxis of a mammal susceptible to or afflicted with transplantationrejection. The methods comprising administering an effectivecondition-treating or condition-preventing amount of one or more of thepharmaceutical compositions or the compound of the invention hereindescribed. In a specific embodiment, the transplantation rejection isorgan transplant rejection, tissue transplant rejection and celltransplant rejection.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in the treatment, and/orprophylaxis of transplantation rejection. In a specific embodiment, thetransplantation rejection is organ transplant rejection, tissuetransplant rejection and cell transplant rejection.

In yet another aspect, provided herein is the use of the compound or thepharmaceutical composition disclosed herein for use in the manufactureof a medicament for the treatment and/or prophylaxis of transplantationrejection. In a specific embodiment, the transplantation rejection isorgan transplant rejection, tissue transplant rejection and celltransplant rejection.

The present invention provides the compound or the pharmaceuticalcomposition disclosed herein for use as a pharmaceutical especially inthe treatment and/or prophylaxis of the aforementioned diseases ordisorders. Also provided herein is the use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment and/or prophylaxis of one of theaforementioned diseases or disorders.

A particular regimen of the present method comprises the administrationto a subject suffering from a disease involving inflammation, of aneffective amount of a compound disclosed herein for a period of timesufficient to reduce the level of inflammation in the subject, andpreferably terminate the processes responsible for said inflammation. Aspecial embodiment of the method comprises administering of an effectiveamount of a compound disclosed herein to a subject patient sufferingfrom or susceptible to the development of rheumatoid arthritis, for aperiod of time sufficient to reduce or prevent, respectively,inflammation in the joints of said patient, and preferably terminate,the processes responsible for said inflammation.

A further particular regimen of the present method comprises theadministration to a subject suffering from a disease involvingproliferative disease, of an effective amount of a compound disclosedherein for a period of time sufficient to reduce the level ofproliferative disease in the subject, and preferably terminate theprocesses responsible for said proliferative disease. A particularembodiment of the method comprises administering of an effective amountof a compound disclosed herein to a subject patient suffering from orsusceptible to the development of cancer, for a period of timesufficient to reduce or prevent, respectively, solid tumor of saidpatient, and preferably terminate, the processes responsible for saidsolid.

Combination Therapy

A compound disclosed herein can be administered as the sole active agentor it can be administered in combination with other therapeutic agents,including other compounds that demonstrate the same or a similartherapeutic activity and that are determined to be safe and efficaciousfor such combined administration.

In one aspect, provided herein is a method of treating, preventing,managing, or ameliorating a disease or disorder comprising administeringa safe and effective amount of a combination comprising the compounddisclosed herein together with one or more therapeutically activeagents. In one embodiment, the combinations comprising one or two othertherapeutic agents.

Example of other therapeutic agents may include without limitationanti-cancer agents, including chemotherapeutic agents andantiproliferative agents; anti-inflammatory agents and immunomodulatoryagents or immunosuppressive agents.

In another aspect, provided herein is a product comprising a compounddisclosed herein and at least one other therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in therapy. Inone embodiment, the therapy is the treatment of a disease or disordermediated by the activity of one or more protein kinases activity, suchas JAK kinases, FLT4 kinase, FLT3 kinase and Aurora kinases. Productsprovided as a combined preparation include a composition comprising thecompound disclosed herein and the other therapeutic agent(s) together inthe same pharmaceutical composition, or the compound disclosed hereinand the other therapeutic agent(s) in separate form, e.g. in the form ofa kit.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound disclosed herein and another therapeutic agent(s).In one embodiment, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, carrier, adjuvant or vehicle asdescribed above.

In another aspect, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound disclosed herein. In one embodiment, the kit comprises meansfor separately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The invention also provides the use of a compound disclosed herein fortreating a disease or condition mediated by the activity of one or moreprotein kinases, such as JAK kinases, FLT4 kinase, FLT3 kinase andAurora kinases, wherein the patient has previously (e.g. within 24hours) been treated with another therapeutic agent. The invention alsoprovides the use of another therapeutic agent for treating a disease orcondition mediated by the activity of one or more protein kinases, suchas JAK kinases, FLT4 kinase, FLT3 kinase and Aurora kinases, wherein thepatient has previously (e.g. within 24 hours) been treated with acompound disclosed herein.

The compounds disclosed herein may be administered as the sole activeingredient or in conjunction with, e.g. as an adjuvant to, othertherapeutic agent.

In one embodiment, other therapeutic agent refers to chemotherapeuticagents or antiproliferative agents. Some non-limiting examples of knownchemotherapeutic agents include other therapies or anticancer agentsthat may be used in combination with the inventive anticancer agents ofthe present invention and include surgery, radiotherapy (in but a fewexamples, gamma radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes, to name a few), endocrine therapy, taxanes (taxol, taxotereetc), platinum derivatives (cisplatin, carboplatin), biologic responsemodifiers (interferons, interleukins), tumor necrosis factor (TNF, TRAILreceptor targeting agents, to name a few), hyperthermia and cryotherapy,agents to attenuate any adverse effects (e.g., antiemetics), and otherapproved chemotherapeutic drugs, including, but not limited to,alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide,melphalan, ifosfamide), antimetabolites (methotrexate, pemetrexed etc),purine antagonists and pyrimidine antagonists (6-mercaptopurine,5-fluorouracil, cytarabile, gemcitabine), spindle poisons (vinblastine,vincristine, vinorelbine), podophyllotoxins (etoposide, irinotecan,topotecan), antibiotics (doxorubicin, bleomycin, mitomycin),nitrosoureas (carmustine, lomustine), cell cycle inhibitors (KSP mitotickinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase),hormones (tamoxifen, leuprolide, flutamide, megestrol, dexamethasone),antiangiogenic agents (avastin and others), monoclonal antibodies(BENLYSTA®), brentuximab (ADCETRIS®), cetuximab (ERBITUX®), gemtuzumab(MYLOTARG®), ipilimumab (YERVOY®), ofatumumab (ARZERRA®), panitumumab(VECTIBIX®), ranibizumab (LUCERTIS®), rituximab (RITUXAN®), tositumomab(BEXXAR®), trastuzumab (HERCEPTIN®)), kinase inhibitors (imatinib(GLEEVEC®), sunitinib (SUTENT®), sorafenib (NEXAVAR®), erlotinib,(TARCEVA®), gefitinib (IRESSA®), dasatinib (SPRYCEL®), nilotinib(TASIGNA®), lapatinib (TYKERB®), crizotinib (XALKORI®), ruxolitinib(JAKAFI®), vemurafenib (ZELBORAF®), vandetanib (CAPRELSA®), pazopanib(VOTRIENT®), and others), and agents inhibiting or activating cancerpathways such as the mTOR, HIF (hypoxia induced factor) pathways (suchas everolimus and temsirolimus) and others. For a more comprehensivediscussion of updated cancer therapies see, http://www.nci.nih.gov/, alist of the FDA approved oncology drugs athttp://www.fda.gov/cder/cancer/druglist-rame.htm, and The Merck Manual,Eighteenth Ed. 2006, all of which are herein incorporated by referencein their entireties. In another embodiment, the compounds of the presentinvention can be combined, with cytotoxic anti-cancer agents. Examplesof such agents can be found in the 13th Edition of the Merck Index(2001). These agents include, by no way of limitation, asparaginase,bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin,doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil,hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin,lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate,mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine,raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine,vincristine and vindesine. Other cytotoxic drugs suitable for use withthe compounds of the invention include, but are not limited to, thosecompounds acknowledged to be used in the treatment of neoplasticdiseases, such as those for example in Goodman and Gilman's ThePharmacological Basis of Therapeutics (Ninth Edition, 1996,McGraw-Hill). These agents include, by no way of limitation,aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidinecladribine, busulfan, diethylstilbestrol, 2,2′-difluorodeoxycytidine,docetaxel, erythrohydroxynonyladenine, ethinyl estradiol,5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabinephosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate,idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate,melphalan, mitotane, paclitaxel, pentostatin,N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide,testosterone propionate, thiotepa, trimethylmelamine, uridine, andvinorelbine.

Other cytotoxic anti-cancer agents suitable for use in combination withthe compounds of the invention also include newly discovered cytotoxicprinciples such as oxaliplatin, vemurafenib, capecitabine, epothiloneand its natural or synthetic derivatives, temozolomide (Quinn et al., J.Clin. Oncol., 2003, 21(4), 646-651), tositumomab (BEXXAR®), trabedectin(Vidal et al., Proceedings of the American Society for ClinicalOncology, 2004, 23, abstract 3181), and the inhibitors of the kinesinspindle protein Eg5 (Wood et al., Curr. Opin. Pharmacol., 2001, 1,370-377).

In another embodiment, the compounds of the present invention can becombined with other signal transduction inhibitors. EGFR family as oneof the target signal transduction inhibitors, such as EGFR, HER-2 andHER-4 (Raymond et al., Drugs, 2000, 60 (Suppl. 1), 15-23; Harari et al.,Oncogene, 2000, 19 (53), 6102-6114) and ligands thereof. Examples ofsuch therapies also include, by no way of limitation, small-moleculekinase inhibitors such as imatinib (GLEEVEC®), sunitinib (SUTENT®),sorafenib (NEXAVAR®), erlotinib (TARCEVA®), gefitinib (IRESSA®),dasatinib (SPRYCEL®), nilotinib (TASIGNA®), lapatinib (TYKERB®),crizotinib (XALKORP)), ruxolitinib (JAKAFI®), vemurafenib (ZELBORAF®),vandetanib (CAPRELSA®), pazopanib (VOTRIENT®), afatinib, alisertib,amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib,cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib,foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib,linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib,oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib,rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib,telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib,veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605,TKI258, GDC-0941 (Folkes et al. J. Med. Chem. 2008, 51: 5522), BZE235,and others.

In one embodiment, the compounds disclosed herein may be administered inconjunction with, e.g. as an adjuvant to, other drugs e.g.immunosuppressive or immunomodulating agents or other anti-inflammatoryagents, e.g. for the treatment or prevention of alio- or xenograft acuteor chronic rejection or inflammatory or autoimmune disorders, or achemotherapeutic agent, e.g a malignant cell anti-proliferative agent.For example, the compounds disclosed herein may be used in combinationwith a calcineurin inhibitor, e.g. cyclosporin A or FK 506; a mTORinhibitor, e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779,ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9; an ascomycin havingimmuno-suppressive properties, e.g. ABT-281, ASM981, etc.;corticosteroids; cyclophosphamide; azathioprene; methotrexate;leflunomide; mizoribine; mycophenolic acid or salt; mycophenolatemofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogueor derivative thereof; a PKC inhibitor, e.g. as disclosed in WO 02/38561or WO 03/82859, e.g. the compound of Example 56 or 70; immunosuppressivemonoclonal antibodies, e.g., monoclonal antibodies to leukocytereceptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45,CD52, CD58, CD80, CD86 or their ligands; other immunomodulatorycompounds, e.g. a recombinant binding molecule having at least a portionof the extracellular domain of CTLA4 or a mutant thereof, e.g. an atleast extracellular portion of CTLA4 or a mutant thereof joined to anon-CTLA4 protein sequence, e.g. CTLA41g (for ex. designated ATCC 68629)or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g.LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4antagonists; or antihistamines; or antitussives, or a bronchodilatoryagent; or an angiotensin receptor blockers; or an anti-infectious agent.

Where the compounds disclosed herein are administered in conjunctionwith other immunosuppressive/immunomodulatory, anti-inflammatory,chemotherapeutic or anti-infectious therapy, dosages of theco-administered immunosuppressant, immunomodulatory, anti-inflammatory,chemotherapeutic or anti-infectious compound will of course varydepending on the type of co-drug employed, e.g. whether it is a steroidor a calcineurin inhibitor, on the specific drug employed, on thecondition being treated and so forth.

In one aspect, provided herein is a combination comprising a compounddisclosed herein together with a β₂-adrenoreceptor agonist. Examples ofβ₂-adrenoreceptor agonists include salmeterol, salbutamol, formoterol,salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol,pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol,terbutaline and salts thereof, for example the xinafoate(1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphatesalt or free base of salbutamol or the fumarate salt of formoterol. Inone embodiment, long-acting β₂-adrenoreceptor agonists, for example,compounds which provide effective bronchodilation for about 12 h orlonger, are preferred.

The β₂-adrenoreceptor agonist may be in the form of a salt formed with apharmaceutically acceptable acid selected from sulphuric, hydrochloric,fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic),cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic,naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic,4-chlorobenzoic and 4-phenylbenzoic acid.

In another aspect, provided herein is a combination comprising acompound disclosed herein together with corticosteroids. Suitablecorticosteroids refer to those oral and inhaled corticosteroids andtheir pro-drugs which have anti-inflammatory activity. Examples includemethyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (fluticasone furoate),6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-ethycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, beclomethasone esters (for example the17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (for example mometasone furoate),triamcinolone acetonide, rofleponide, ciclesonide(16α,17-[[(cis)-cyclohexylmethylene]bis(oxy)]-11β,21-dihydroxy-pregna-1,4-diene-3,20-dione),butixocort propionate, RPR-106541, and ST-126. Preferred corticosteroidsinclude fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic acidS-fluoromethyl ester. In one embodiment the corticosteroid is6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

In another aspect, provided herein is a combination comprising acompound disclosed herein together with non-steroidal GR agonist.Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful in combination therapy include those covered in the followingpatents: WO 03/082827, WO 98/54159, WO 04/005229, WO 04/009017, WO04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO03/101932, WO 02/02565, WO 01/16128, WO 00/66590, WO 03/086294, WO04/026248, WO 03/061651 and WO 03/08277. Further non-steroidal compoundsare covered in: WO 2006/000401, WO 2006/000398 and WO 2006/015870.

In another aspect, provided herein is a combination comprising acompound disclosed herein together with non-steroidal anti-inflammatorydrugs (NSAID's). Examples of NSAID's include sodium cromoglycate,nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example,theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors),leukotriene antagonists, inhibitors of leukotriene synthesis (forexample montelukast), iNOS inhibitors, tryptase and elastase inhibitors,beta-2 integrin antagonists and adenosine receptor agonists orantagonists (e.g. adenosine 2a agonists), cytokine antagonists (forexample chemokine antagonists, such as a CCR3 antagonist) or inhibitorsof cytokine synthesis, or 5-lipoxygenase inhibitors. An iNOS (induciblenitric oxide synthase inhibitor) is preferably for oral administration.Examples of iNOS inhibitors include those disclosed in WO 93/13055, WO98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Examples of CCR3inhibitors include those disclosed in WO 02/26722.

In one embodiment, the invention provides the use of the compoundsdisclosed herein in combination with a phosphodiesterase 4 (PDE4)inhibitor, especially in the case of a formulation adapted forinhalation. The PDE4-specific inhibitor useful in this aspect of theinvention may be any compound that is known to inhibit the PDE4 enzymeor which is discovered to act as a PDE4 inhibitor, and which are onlyPDE4 inhibitors, not compounds which inhibit other members of the PDEfamily, such as PDE3 and PDE5, as well as PDE4. Compounds includecis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].Also,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomilast) and its salts, esters, pro-drugs orphysical forms, which is described in U.S. Pat. No. 5,552,438 issued 3Sep. 1996; this patent and the compounds it discloses are incorporatedherein in full by reference.

In another aspect, provided herein is a combination comprising acompound disclosed herein together with an anticholinergic agent.Examples of anticholinergic agents are those compounds that act asantagonists at the muscarinic receptors, in particular those compoundswhich are antagonists of the M₁ or M₃ receptors, dual antagonists of theM₁/M₃ or M₂/M₃, receptors or pan-antagonists of the M₁/M₂/M₃ receptors.Exemplary compounds for administration via inhalation includeipratropium (for example, as the bromide, CAS 22254-24-6, sold under thename ATROVENT®), oxitropium (for example, as the bromide, CAS30286-75-0) and tiotropium (for example, as the bromide, CAS136310-93-5, sold under the name SPIRIVA®). Also of interest arerevatropate (for example, as the hydrobromide, CAS 262586-79-8) andLAS-34273 which is disclosed in WO 01/04118. Exemplary compounds fororal administration include pirenzepine (CAS 28797-61-7), darifenacin(CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under thename ENABLER®), oxybutynin (CAS 5633-20-5, sold under the nameDITROPAN®), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5,or CAS 124937-52-6 for the tartrate, sold under the name DETROL®),otilonium (for example, as the bromide, CAS 26095-59-0, sold under thename SPASMOMEN®), trospium chloride (CAS 10405-02-4) and solifenacin(CAS 242478-37-1, or CAS 242478-38-2 for the succinate also known asYM-905 and sold under the name VESICARE®).

In another aspect, provided herein is a combination comprising acompound disclosed herein together with an H1 antagonist. Examples of H1antagonists include, without limitation, amelexanox, astemizole,azatadine, azelastine, acrivastine, brompheniramine, cetirizine,levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine,carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine,doxylamine, dimethindene, ebastine, epinastine, efletirizine,fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine,mizolastine, mequitazine, mianserin, noberastine, meclizine,norastemizole, olopatadine, picumast, pyrilamine, promethazine,terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine,particularly cetirizine, levocetirizine, efletirizine and fexofenadine.In a further embodiment the invention provides a combination comprisinga compound disclosed herein together with an H3 antagonist (and/orinverse agonist). Examples of H3 antagonists include, for example, thosecompounds disclosed in WO 2004/035556 and in WO 2006/045416. Otherhistamine receptor antagonists which may be used in combination with thecompounds disclosed herein include antagonists (and/or inverse agonists)of the H4 receptor, for example, the compounds disclosed in Jablonowskiet al., J. Med. Chem., 2003, 46:3957-3960.

In still another aspect, provided herein is a combination comprising acompound disclosed herein together with a PDE4 inhibitor and a02-adrenoreceptor agonist.

In yet another aspect, provided herein is a combination comprising acompound disclosed herein together with an anticholinergic and a PDE-4inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus pharmaceuticalcompositions comprising a combination as defined above together with apharmaceutically acceptable excipient or carrier represent a furtheraspect of the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. In one embodiment, the individual compounds will beadministered simultaneously in a combined pharmaceutical formulation.Appropriate doses of known therapeutic agents will readily beappreciated by those skilled in the art.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound disclosed hereintogether with another therapeutically active agent.

In one embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with achemotherapeutic agents.

In one embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with ananti-proliferative agents.

In one embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with a PDE4inhibitor.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with aβ2-adrenoreceptor agonist.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with acorticosteroid.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with a non-steroidalGR agonist.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with ananticholinergic agent.

In still another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with anantihistamine.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with ananti-inflammatory agents.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with animmunomodulators.

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with an agents fortreating atherosclerosis

In another embodiment, the pharmaceutical composition comprises acombination of a compound disclosed herein together with an agents fortreating pulmonary fibrosis.

In the field of medical oncology it is normal practice to use acombination of different forms of treatment to treat each patient withcancer. In medical oncology the other component(s) of such conjointtreatment in addition to compositions disclosed herein may be, forexample, surgery, radiotherapy, chemotherapy, signal transductioninhibitors or modulators (e.g. kinase inhibitors or modulators) and/ormonoclonoal antibodies.

A compound disclosed herein may also be used to advantage in combinationwith each other or in combination with other therapeutic agents,especially other antiproliferative agents. Such antiproliferative agentsinclude, but are not limited to, aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive agents; alkylating agents; histone deacetylase inhibitors;compounds that induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; agents used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors; temozolomide (TEMODAL®); and leucovorin.

The term “aromatase inhibitor”, as used herein, relates to a compoundwhich inhibits the estrogen production, i.e., the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to, steroids,especially atamestane, exemestane and formestane; and, in particular,nonsteroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g., under the trademarkAROMASIN®. Formestane can be administered, e.g., in the form as it ismarketed, e.g., under the trademark LENTARON®. Fadrozole can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark AFEMA®. Anastrozole can be administered, e.g., in the form asit is marketed, e.g., under the trademark ARIMIDEX®. Letrozole can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark FEMARA® or FEMAR®. Aminoglutethimide can be administered,e.g., in the form as it is marketed, e.g., under the trademarkORIMETEN®. A combination of the invention comprising a chemotherapeuticagent which is an aromatase inhibitor is particularly useful for thetreatment of hormone receptor positive tumors, e.g., breast tumors.

The term “anti-estrogen”, as used herein, relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to, tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g., under the trademark NOLVADEX®.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g., under the trademark EVISTA®. Fulvestrant can beformulated as disclosed in U.S. Pat. No. 4,659,516 or it can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark FASLODEX®. A combination of the invention comprising achemotherapeutic agent which is an antiestrogen is particularly usefulfor the treatment of estrogen receptor positive tumors, e.g., breasttumors.

The term “anti-androgen”, as used herein, relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX®), which canbe formulated, e.g., as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist”, as used herein, includes, but is notlimited to, abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g., under the trademark ZOLADEX®. Abarelixcan be formulated, e.g., as disclosed in U.S. Pat. No. 5,843,901. Theterm “topoisomerase I inhibitor”, as used herein, includes, but is notlimited to, topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO 99/17804). Irinotecan can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark CAMPTOSAR®. Topotecan can be administered, e.g., in the formas it is marketed, e.g., under the trademark HYCAMTIN®.

The term “topoisomerase II inhibitor”, as used herein, includes, but isnot limited to, the anthracyclines, such as doxorubicin, includingliposomal formulation, e.g., CAELYX®; daunorubicin; epirubicin;idarubicin; nemorubicin; the anthraquinones mitoxantrone andlosoxantrone; and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g., in the form as it is marketed,e.g., under the trademark ETOPOPHOS®. Teniposide can be administered,e.g., in the form as it is marketed, e.g., under the trademark VM26-BRISTOL®. Doxorubicin can be administered, e.g., in the form as it ismarketed, e.g., under the trademark ADRIBLASTIN® or ADRIAMYCIN®.

Epirubicin can be administered, e.g., in the form as it is marketed,e.g., under the trademark FARMORUBICIN®. Idarubicin can be administered,e.g., in the form as it is marketed, e.g., under the trademark ZAVEDOS®.Mitoxantrone can be administered, e.g., in the form as it is marketed,e.g., under the trademark NOVANTRON®.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing agents and microtublin polymerizationinhibitors including, but not limited to, taxanes, e.g., paclitaxel anddocetaxel; vinca alkaloids, e.g., vinblastine, especially vinblastinesulfate; vincristine, especially vincristine sulfate and vinorelbine;discodermolides; cochicine; and epothilones and derivatives thereof,e.g., epothilone B or D or derivatives thereof. Paclitaxel may beadministered, e.g., in the form as it is marketed, e.g., TAXOL®.Docetaxel can be administered, e.g., in the form as it is marketed,e.g., under the trademark TAXOTERE®. Vinblastine sulfate can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark VINBLASTIN R.P®. Vincristine sulfate can be administered,e.g., in the form as it is marketed, e.g., under the trademarkFARMISTIN®. Discodermolide can be obtained, e.g., as disclosed in U.S.Pat. No. 5,010,099. Also included are epothilone derivatives which aredisclosed in WO 98/10121, U.S. Pat. No. 6,194,181, WO 98/25929, WO98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Especially preferredare epothilone A and/or B.

The term “alkylating agent”, as used herein, includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g., under the trademark CYCLOSTIN®. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark HOLOXAN®.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds disclosed in WO02/22577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU; capecitabine; gemcitabine; DNA demethylatingagents, such as 5-azacytidine and decitabine; methotrexate andedatrexate; and folic acid antagonists, such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g., underthe trademark XELODA®. Gemcitabine can be administered, e.g., in theform as it is marketed, e.g., under the trademark GEMZAR®. Also includedis the monoclonal antibody trastuzumab which can be administered, e.g.,in the form as it is marketed, e.g., under the trademark HERCEPTIN®.

The term “platin compound”, as used herein, includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g., underthe trademark CARBOPLAT®. Oxaliplatin can be administered, e.g., in theform as it is marketed, e.g., under the trademark ELOXATIN®.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds”, as used herein, includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, e.g.,

-   a) compounds targeting, decreasing or inhibiting the activity of the    platelet-derived growth factor-receptors (PDGFR), such as compounds    which target, decrease or inhibit the activity of PDGFR, especially    compounds which inhibit the PDGF receptor, e.g., a    N-phenyl-2-pyrimidine-amine derivative, e.g., imatinib, SU101,    SU6668 and GFB-111;-   b) compounds targeting, decreasing or inhibiting the activity of the    fibroblast growth factor-receptors (FGFR);-   c) compounds targeting, decreasing or inhibiting the activity of the    insulin-like growth factor receptor I (IGF-IR), such as compounds    which target, decrease or inhibit the activity of IGF-IR, especially    compounds which inhibit the IGF-IR receptor, such as those compounds    disclosed in WO 02/092599;-   d) compounds targeting, decreasing or inhibiting the activity of the    Trk receptor tyrosine kinase family;-   e) compounds targeting, decreasing or inhibiting the activity of the    Axl receptor tyrosine kinase family;-   f) compounds targeting, decreasing or inhibiting the activity of the    c-Met receptor;-   g) compounds targeting, decreasing or inhibiting the activity of the    Kit/SCFR receptor tyrosine kinase;-   h) compounds targeting, decreasing or inhibiting the activity of the    c-kit receptor tyrosine kinases—(part of the PDGFR family), such as    compounds which target, decrease or inhibit the activity of the    c-Kit receptor tyrosine kinase family, especially compounds which    inhibit the c-Kit receptor, e.g., imatinib;-   i) compounds targeting, decreasing or inhibiting the activity of    members of the c-Abl family and their gene-fusion products, e.g.,    BCR-Abl kinase, such as compounds which target decrease or inhibit    the activity of c-Abl family members and their gene fusion products,    e.g., a N-phenyl-2-pyrimidine-amine derivative, e.g., imatinib,    PD180970, AG957, NSC 680410 or PD173955 from ParkeDavis;-   j) compounds targeting, decreasing or inhibiting the activity of    members of the protein kinase C (PKC) and Raf family of    serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK and    Ras/MAPK family members, or PI(3) kinase family, or of the    PI(3)-kinase-related kinase family, and/or members of the    cyclin-dependent kinase family (CDK) and are especially those    staurosporine derivatives disclosed in U.S. Pat. No. 5,093,330,    e.g., midostaurin; examples of further compounds include, e.g.,    UCN-01; safingol; BAY 43-9006; Bryostatin 1; Perifosine; llmofosine;    RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196;    isochinoline compounds, such as those disclosed in WO 00/09495;    FTIs; PD184352; or QAN697 (a PI3K inhibitor);-   k) compounds targeting, decreasing or inhibiting the activity of    protein-tyrosine kinase inhibitors, such as compounds which target,    decrease or inhibit the activity of protein-tyrosine kinase    inhibitors include imatinib mesylate (GLEEVEC®) or tyrphostin. A    tyrphostin is preferably a low molecular weight (Mr<1500) compound,    or a pharmaceutically acceptable salt thereof, especially a compound    selected from the benzylidenemalonitrile class or the    S-arylbenzenemalonirile or bisubstrate quinoline class of compounds,    more especially any compound selected from the group consisting of    Tyrphostin A23/RG-50810, AG 99, Tyrphostin AG 213, Tyrphostin AG    1748, Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44 (+)    enantiomer, Tyrphostin AG 555, AG 494, Tyrphostin AG 556, AG957 and    adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid    adamantyl ester, NSC 680410, adaphostin; and 1) compounds targeting,    decreasing or inhibiting the activity of the epidermal growth factor    family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as    homo- or hetero-dimers), such as compounds which target, decrease or    inhibit the activity of the epidermal growth factor receptor family    are especially compounds, proteins or antibodies which inhibit    members of the EGF receptor tyrosine kinase family, e.g., EGF    receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related    ligands, and are in particular those compounds, proteins or    monoclonal antibodies generically and specifically disclosed in WO    97/02266, e.g., the compound of Example 39, or in EP 0564409; WO    99/03854; EP 0520722; EP 0566226; EP 0787722; EP 0837063; U.S. Pat.    No. 5,747,498; WO 98/10767; WO 97/30034; WO 97/49688; WO 97/38983    and, especially, WO 96/30347, e.g., compound known as CP 358774; WO    96/33980, e.g., compound ZD 1839; and WO 95/03283, e.g., compound    ZM105180, e.g., trastuzumab (HERCEPTIN), cetuximab, Iressa, Tarceva,    OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4,    E2.11, E6.3 or E7.6.3; and 7H-pyrrolo[2,3-d]pyrimidine derivatives    which are disclosed in WO 03/013541.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g., unrelated to protein or lipid kinaseinhibition, e.g., thalidomide (THALOMID®) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are, e.g., inhibitors of phosphatase 1, phosphatase2A, PTEN or CDC25, e.g., okadaic acid or a derivative thereof.

Compounds that induce cell differentiation processes are e.g. retinoicacid, α-, γ- or δ-tocopherol or α-, γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor, as used herein, includes, but is notlimited to, e.g., Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX®), rofecoxib (VIOXX®), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.,5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid orlumiracoxib.

The term “bisphosphonates”, as used herein, includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark DIDRONEL®. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g., under the trademark BONEFOS®. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.,under the trademark SKELID®. “Pamidronic acid” can be administered,e.g., in the form as it is marketed, e.g., under the trademark AREDIA™“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g., under the trademark FOSAMAX®. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g., under thetrademark BONDRANAT®. “Risedronic acid” can be administered, e.g., inthe form as it is marketed, e.g., under the trademark ACTONEL®.“Zoledronic acid” can be administered, e.g., in the form as it ismarketed, e.g., under the trademark ZOMETA®.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “heparanase inhibitor”, as used herein, refers to compoundswhich target, decrease or inhibit heparin sulphate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier”, as used herein, refers to alymphokine or interferons, e.g., interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g., H-Ras, K-Ras orN-Ras, as used herein, refers to compounds which target, decrease orinhibit the oncogenic activity of Ras, e.g., a “farnesyl transferaseinhibitor”, e.g., L-744832, DK8G557 or R1 15777 (Zarnestra).

The term “telomerase inhibitor”, as used herein, refers to compoundswhich target, decrease or inhibit the activity of telomerase. Compoundswhich target, decrease or inhibit the activity of telomerase areespecially compounds which inhibit the telomerase receptor, e.g.,telomestatin.

The term “methionine aminopeptidase inhibitor”, as used herein, refersto compounds which target, decrease or inhibit the activity ofmethionine aminopeptidase. Compounds which target, decrease or inhibitthe activity of methionine aminopeptidase are, e.g., bengamide or aderivative thereof.

The term “proteasome inhibitor”, as used herein, refers to compoundswhich target, decrease or inhibit the activity of the proteasome.Compounds which target, decrease or inhibit the activity of theproteasome include, e.g., PS-341 and MLN 341.

The term “matrix metalloproteinase inhibitor” or “MMP inhibitor”, asused herein, includes, but is not limited to, collagen peptidomimeticand nonpeptidomimetic inhibitors, tetracycline derivatives, e.g.,hydroxamate peptidomimetic inhibitor batimastat and its orallybioavailable analogue marimastat (BB-2516), prinomastat (AG3340),metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B orAAJ996.

The term “agents used in the treatment of hematologic malignancies”, asused herein, includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, e.g., compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,e.g., compounds which target, decrease or inhibit anaplastic lymphomakinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,e.g., PKC412, midostaurin, a staurosporine derivative, SU1 1248 andMLN518.

The term “HSP90 inhibitors”, as used herein, includes, but is notlimited to, compounds targeting, decreasing or inhibiting the intrinsicATPase activity of HSP90; degrading, targeting, decreasing or inhibitingthe HSP90 client proteins via the ubiquitin proteasome pathway.Compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90 are especially compounds, proteins or antibodies whichinhibit the ATPase activity of HSP90, e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative, othergeldanamycin related compounds, radicicol and HDAC inhibitors.

The term “antiproliferative antibodies”, as used herein, includes, butis not limited to, trastuzumab (HERCEPTIN™), Trastuzumab-DM1, erlotinib(TARCEVA™), bevacizumab (AVASTIN™), rituximab (RITUXAN®), PR064553(anti-CD40) and 2C4 antibody. By antibodies is meant, e.g., intactmonoclonal antibodies, polyclonal antibodies, multispecific antibodiesformed from at least two intact antibodies, and antibodies fragments solong as they exhibit the desired biological activity. For the treatmentof acute myeloid leukemia (AML), compounds disclosed herein can be usedin combination with standard leukemia therapies, especially incombination with therapies used for the treatment of AML. In particular,compounds disclosed herein can be administered in combination with,e.g., farnesyl transferase inhibitors and/or other drugs useful for thetreatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

A compound disclosed herein may also be used to advantage in combinationwith each other or in combination with other therapeutic agents,especially other anti-malarial agents. Such anti-malarial agentsinclude, but are not limited to proguanil, chlorproguanil, trimethoprim,chloroquine, mefloquine, lumefantrine, atovaquone,pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine,quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin,arteflene, artemether, artesunate, primaquine, inhaled NO, L-arginine,Dipropylenetri-amine NONOate (NO donor), Rosiglitzone (PPAR-γ agonist),activated charcoal, Erythropoietin, Levamisole, and pyronaridine.

A compound disclosed herein may also be used to advantage in combinationwith each other or in combination with other therapeutic agents, such asused for the treatment of Leishmaniosis, Trypanosomiasis, Toxoplasmosisand Neurocysticercosis. Such agents include, but are not limited tochloroquine sulfate, atovaquone-proguanil, artemether-lumefantrine,quinine-sulfate, artesunate, quinine, doxycycline, clindamycin,meglumine antimoniate, sodium stibogluconate, miltefosine, ketoconazole,pentamidine, amphotericin B (AmB), liposomal-AmB, paromomycine,eflornithine, nifurtimox, suramin, melarsoprol, prednisolone,benznidazole, sulfadiazine, pyrimethamine, clindamycin, trimetropim,sulfamethoxazole, azitromycin, atovaquone, dexamethasone, praziquantel,albendazole, beta-lactams, fluoroquinolones, macrolides,aminoglycosides, sulfadiazine and pyrimethamine.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g., PatentsInternational, e.g., IMS World Publications.

The above-mentioned compounds, which can be used in combination with acompound disclosed herein, can be prepared and administered as describedin the art, such as in the documents cited above.

A compound disclosed herein may also be used to advantage in combinationwith known therapeutic processes, e.g., the administration of hormonesor especially radiation. A compound disclosed herein may in particularbe used as a radiosensitizer, especially for the treatment of tumorswhich exhibit poor sensitivity to radiotherapy.

By “combination”, there is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound disclosed herein and a combination partner may beadministered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g., synergistic, effect or any combination thereof. Theterms “coadministration” or “combined administration” or the like asutilized herein are meant to encompass administration of the selectedcombination partner to a single subject in need thereof (e.g. apatient), and are intended to include treatment regimens in which theagents are not necessarily administered by the same route ofadministration or at the same time. The term “pharmaceuticalcombination” as used herein means a product that results from the mixingor combining of more than one active ingredient and includes both fixedand non-fixed combinations of the active ingredients. The term “fixedcombination” means that the active ingredients, e.g. a compounddisclosed herein and a combination partner, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound disclosed herein and a combination partner, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

Methods of Treatment

In one embodiment, the methods of treatment disclosed herein compriseadministering a safe and effective amount of a compound or apharmaceutically composition disclosed herein to a patient in needthereof. Individual embodiments disclosed herein include methods oftreating any one of the above-mentioned disorders by administering asafe and effective amount of a compound disclosed herein or apharmaceutical composition containing a compound disclosed herein to apatient in need thereof.

In one embodiment, the compounds disclosed herein or pharmaceuticallycompositions containing the compounds disclosed herein may beadministered by any suitable route of administration, including bothsystemic administration and topical administration. Systemicadministration includes oral administration, parenteral administration,transdermal administration and rectal administration. Parenteraladministration is typically by injection or infusion, includingintravenous, intramuscular, and subcutaneous injection or infusion.Topical administration includes application to the skin as well asintraocular, otic, intravaginal, inhaled and intranasal administration.In one embodiment, the compounds disclosed herein or pharmaceuticalcompositions containing the compounds disclosed herein may beadministered orally. In another embodiment, the compounds disclosedherein or pharmaceutically compositions containing the compoundsdisclosed herein may be administered by inhalation. In a furtherembodiment, the compounds disclosed herein or pharmaceuticalcompositions containing the compounds disclosed herein may beadministered intranasally.

In another embodiment, the compounds disclosed herein orpharmaceutically compositions containing the compounds disclosed hereinmay be administered once or according to a dosing regimen wherein anumber of doses are administered at varying intervals of time for agiven period of time. For example, doses may be administered one, two,three, or four times per day. In one embodiment, a dose is administeredonce per day. In a further embodiment, a dose is administered twice perday. Doses may be administered until the desired therapeutic effect isachieved or indefinitely to maintain the desired therapeutic effect.Suitable dosing regimens for a compound disclosed herein or apharmaceutical composition containing a compound disclosed herein dependon the pharmacokinetic properties of that compound, such as absorption,distribution, and half-life, which can be determined by the skilledartisan. In addition, suitable dosing regimens, including the durationsuch regimens are administered, for a compound disclosed herein or apharmaceutical composition containing a compound disclosed herein dependon the disorder being treated, the severity of the disorder beingtreated, the age and physical condition of the patient being treated,the medical history of the patient to be treated, the nature ofconcurrent therapy, the desired therapeutic effect, and like factorswithin the knowledge and expertise of the skilled artisan. It will befurther understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's responseto the dosing regimen or over time as individual patient needs change.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease. The above-cited dosageproperties are demonstrable in vitro and in vivo tests usingadvantageously mammals, e.g., mice, rats, dogs, monkeys or isolatedorgans, tissues and preparations thereof. The compounds of the presentinvention can be applied in vitro in the form of solutions, e.g.,aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution.

In one embodiment, the therapeutically effective dose is from about 0.1mg to about 2,000 mg per day of a compound provided herein. Thepharmaceutical compositions therefore should provide a dosage of fromabout 0.1 mg to about 2000 mg of the compound. In certain embodiments,pharmaceutical dosage unit forms are prepared to provide from about 1 mgto about 2000 mg, from about 10 mg to about 1000 mg, from about 20 mg toabout 500 mg or from about 25 mg to about 250 mg of the essential activeingredient or a combination of essential ingredients per dosage unitform. In certain embodiments, the pharmaceutical dosage unit forms areprepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg,500 mg, 1000 mg or 2000 mg of the essential active ingredient.

Additionally, the compounds disclosed herein may be administered asprodrugs. As used herein, a “prodrug” of a compound disclosed herein isa functional derivative of the compound which, upon administration to apatient, eventually liberates the compound disclosed herein in vivo.Administration of a compound disclosed herein as a prodrug may enablethe skilled artisan to do one or more of the following: (a) modify theonset of the activity of the compound in vivo; (b) modify the durationof action of the compound in vivo; (c) modify the transportation ordistribution of the compound in vivo; (d) modify the solubility of thecompound in vivo; and (e) overcome a side effect or other difficultyencountered with the compound. Typical functional derivatives used toprepare prodrugs include modifications of the compound that arechemically or enzymatically cleavable in vivo. Such modifications, whichinclude the preparation of phosphates, amides, esters, thioesters,carbonates, and carbamates, are well known to those skilled in the art.

General Synthetic Procedures

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention.

Generally, the compounds in this invention may be prepared by methodsdescribed herein, wherein the substituents are as defined for Formula(I), above, except where further noted. The following non-limitingschemes and examples are presented to further exemplify the invention.Persons skilled in the art will recognize that the chemical reactionsdescribed herein may be readily adapted to prepare a number of othercompounds of the invention, and alternative methods for preparing thecompounds of this invention are deemed to be within the scope of thisinvention. For example, the synthesis of non-exemplified compoundsaccording to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company and Alfa Chemical Company, Shanghai Medpep. Co Ltd,Aladdin-Shanghai Jinchun Reagents, Ltd, and were used without furtherpurification unless otherwise indicated. Common solvents were purchasedfrom commercial suppliers such as Shantou XiLong Chemical Factory,Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou ReagentChemical Factory, Tainjin YuYu Fine Chemical Ltd., Qingdao TenglongReagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous THF, dioxane, toluene, and ether were obtained by refluxingthe solvent with sodium. Anhydrous CH₂Cl2 and CHCl3 were obtained byrefluxing the solvent with CaH2. EtOAc, PE, hexanes, DMA and DMF weretreated with anhydrous Na2SO₄ prior use.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was conducted using a silica gel column. Silicagel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

¹H NMR spectra were recorded with a Bruker 400 MHz or 600 MHzspectrometer at ambient temperature. ¹H NMR spectra were obtained asCDCl₃, D₂O, DMSO-d₆, CD₃OD or acetone-d₆ solutions (reported in ppm),using TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard.When peak multiplicities are reported, the following abbreviations areused: s (singlet), d (doublet), t (triplet), m (multiplet), br(broadened), dd (doublet of doublets), ddd (doublet of doublet ofdoublets), dddd (doublet of doublet of doublet of doublets), dt (doubletof triplets), td (triplet of doublets). Coupling constants J, whengiven, are reported in Hertz (Hz). Low-resolution mass spectral (MS)data were generally determined on an Agilent 6120 quadrupole HPLC-MS(Zorbax SB-C18, 2.1×30 mm, 3.5 micron, 6 minutes run, 0.6 mL/min flowrate, 5% to 95% (0.1% formic acid in CH₃CN) in (0.1% formic acid inH₂O)) with UV detection at 210/254 nm and electrospray ionization (ESI).

Purities of compounds were assessed by Agilent 1260 pre-HPLC or Caleseppump 250 pre-HPLC (column: NOVASEP 50/80 mm DAC) with UV detection at210 nm and 254 nm. The following abbreviations are used throughout thespecification:

-   AcOH, HAc, CH₃COOH acetic acid-   Ac₂O acetic anhydride-   BnBr benzyl bromide-   BOC, Boc butyloxycarbony-   (Boc)₂O di-tert-butyl dicarbonate-   BINAP (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   n-BuOH n-butyl alcohol-   BSA benzenesulfonamide-   Cs₂CO₃ cesium carbonate-   CH₂Cl₂, DCM methylene chloride-   CDCl₃ chloroform deuterated-   CH₃I iodomethane-   DIEA, DIPEA, i-Pr2NEt N,N-diisopropylethylamine-   DMF dimethylformamide-   DMAP 4-dimethylaminopyridine-   DMSO dimethylsulfoxide-   DB U 1,8-diazabicyclo[5.4.0]undec-7-ene-   PPTs pyridinium toluene-4-sulphonate-   Et₃N, TEA triethylamine-   EtOAc, EA ethyl acetate-   EtOH ethanol-   Et₂O diethyl ether-   g gram-   h hour-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N,N-Tetramethyluronium    Hexafluorophosphate-   HCl hydrochloric acid-   KOH potassium hydroxide-   K₂CO₃ potassium carbonate-   LAH lithium aluminium hydride-   LDA lithium diisopropylamide-   MeCN, CH₃CN acetonitrile-   MSCl methanesulfonyl chloride-   mCPBA 3-chloroperoxybenzoic acid-   (NH₄)₂SO₄ ammonium sulfate-   NH₄Cl ammonium chloride-   NaH sodium hydride-   Na₂CO₃ sodium carbonate-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   NaOMe sodium methoxide-   Na₂SO₄ sodium sulfate-   Na₂S₂O₃ sodium thiosulfate-   NaOAc ammonium acetate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NIS N-iodosuccinimide-   MeOH methanol-   mL, ml milliliter-   Pd/C palladium on carbon-   PTSA p-toluenesulfonic acid-   PE petroleum ether (60-90° C.)-   PDC pyridinium dichromate-   RT, rt, r.t. room temperature-   PTSA p-toluenesulfonamide-   Pd(OAc)₂ palladium diacetate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(O)-   Pd/C palladium on activated carbon-   Pd(OH)₂/C palladium hydroxide on carbon-   PDC pyridinium dichromate-   Raney Ni Raney Nickel-   Rt retention time-   t-BuONa sodium tert-butoxide-   THF tetrahydrofuran-   TBAF tetrabutylammonium fluoride-   TFAA trifluoroacetic anhydride-   TFA, CF₃COOH trifluoroacetic acid-   Ti(Oi-Pr)₄ titanium tetraisopropanolate-   TsCl tosyl chloride-   Xantphos 4,5-B is (diphenylpho sphino)-9,9-dimethylxanthene

Representative synthetic procedures for the preparation of the compoundsdisclosed herein is outlined below in following Scheme 1 to Scheme 2.Unless otherwise indicated, each Z, A, W, T, R¹, R², R³, R⁴, and R⁵carries the definitions set forth above in connection with Formula (I);each p, q and t is independently 0, 1, 2, 3, 4 or 5; each s isindependently 0 or 1; each PG and PG′ is independently protecting group.

Some compounds having Formula (8) can be prepared by a general methodillustrated in Scheme 1 and described in details in the Examples. Asshowing in Scheme 1, heteroaryl compound (1) is reacted with substitutedheterocyclic compound (2) with an aid of a base, such as Et₃N, DIPEA togive substituted heteroaryl compound (3). The protecting group ofcompound (3) is removed under acidic conditions, such as trifluoroaceticacid, and a solution of HCl in EtOAc, to give the compound (4). Then,compound (4) is reacted with substituted dichloropyrimidine (5) to givecompound (6). Compound (6) is coupled with substituted heteroarylcompound (7) with an aid of a base, such as DIPEA, Et₃N, and in thepresence of a suitable Pd catalyst, such as Pd(OAc)₂, Pd₂(dba)₃ toafford the desired protein kinase inhibitor

Some compounds having Formula (8) also can be prepared by a generalmethod illustrated in Scheme 2 and described in details in the Examples.As showing in Scheme 2, substituted dichloropyrimidine (5) is reactedwith substituted heterocyclic compound (2) with an aid of a base, suchas Et₃N, DIPEA to give compound (10). Compound (10) is coupled withsubstituted heteroaryl compound (7) in the presence of a base, such asDIPEA, Et₃N, and in the presence of a suitable Pd catalyst, such asPd(OAc)₂, Pd₂(dba)₃ to afford the compound (11). The protecting group ofcompound (11) is removed under acidic conditions, such astrifluoroacetic acid, a solution of HCl in EtOAc, to give the compound(12). Compound (12) is reacted with heteroaryl compound (1) with an aidof a base, such as Et₃N, DIPEA to to afford the desired protein kinaseinhibitor (8).

EXAMPLES Example 16-(4-((5-chloro-2-(pyrazolo[1,5-a]pyridin-6-ylamino)pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)nicotinonitrile

Step 1) N-(diphenylmethylene)pyrazolo[1,5-a]pyridin-6-amine

Under N₂ atmosphere, to a mixture of 6-bromopyrazolo[1,5-a]pyridine (1g, 5.0754 mmol), Pd₂(dba)₃ (403.5 mg, 0.4406 mmol), BINAP (312.4 mg,0.5017 mmol), t-BuONa (982.6 mg, 10.22 mmol) and diphenylmethanimine(1.842 g, 10.17 mmol) was added toluene (25 mL). The reaction mixturewas heated to 80° C. and stirred for 6.5 h, and then the reaction wasquenched with water (80 mL). The resulting mixture was extracted withEtOAc (100 mL×3) and the combined organic layers were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=15/1) togive the title compound as a yellow solid (1.42 g, yield 94%).

MS (ESI, pos.ion) m/z: 298.05 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02 (s, 1H), 7.83 (d, J=2.3 Hz, 1H),7.78-7.74 (m, 2H), 7.50 (t, J=7.3 Hz, 1H), 7.42 (t, J=7.5 Hz, 2H), 7.31(ddd, J=14.3, 7.0, 4.2 Hz, 4H), 7.19 (dt, J=5.3, 4.5 Hz, 2H), 6.65 (dd,J=9.3, 1.7 Hz, 1H), 6.40 (d, J=2.0 Hz, 1H).

Step 2) pyrazolo[1,5-a]pyridin-6-amine

N-(diphenylmethylene)pyrazolo[1,5-a]pyridin-6-amine (1.42 g, 4.77 mmol)was dissolved in a solution of hydrogen chloride in EtOAc (20 mL, 60mmol, 3 M), and the reaction mixture was stirred at rt overnight. Thereaction mixture was washed with water (50 mL×2), the separated aqueouslayers were combined and adjusted to pH=10 with saturated Na₂CO₃ aqueoussolution. The resulting mixture was extracted with a mixed solvent ofDCM/MeOH (10/1 (v/v), 150 mL×4). The combined organic layers were driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by silica gel column chromatography (DCM/(a solution of NH₃in MeOH (7 M)) (v/v)=100/1) to give the title compound as a yellow solid(510 mg, yield 80%).

MS (ESI, pos.ion) m/z: 134.20 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.98 (d, J=0.7 Hz, 1H), 7.77 (d, J=2.1Hz, 1H), 7.37 (d, J=9.3 Hz, 1H), 6.74 (dd, J=9.3, 1.4 Hz, 1H), 6.41 (d,J=2.0 Hz, 1H), 3.40 (s, 2H).

Step 3) tert-butyl(1-(5-cyanopyridin-2-yl)piperidin-4-yl)(methyl)carbamate

To a solution of 6-chloronicotinonitrile (200 mg, 1.44 mmol) andtert-butyl methyl(piperidin-4-yl)carbamate (620 mg, 2.88 mmol) in DMF(20 mL) was added K₂CO₃ (600 mg, 4.32 mmol). The reaction mixture wasstirred at 120° C. for 2 hours, and then cooled to room temperature andconcentrated in vacuo. The residue was dissolved in DCM (40 mL) and theresulting mixture was washed with water (20 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel column chromatography (100% DCM) to give the title compoundas a white solid (394 mg, yield 86%).

MS (ESI, pos. ion) m/z: 316.8 [M+H]⁺;

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.45 (s, 9H), 1.55-1.69 (m, 2H),1.80-1.74 (m, 2H), 2.70 (s, 4H), 2.91-3.01 (m, 1H), 4.51-4.56 (m, 3H),6.61 (d, J=9 Hz, 1H), 7.60 (dd, J=2.4 Hz, J=9 Hz, 1H), 8.40 (d, J=2.4Hz, 1H).

Step 4) (6-(4-(methyl)amino)piperidin-1-yl)nicotinonitrile

To a solution of tert-butyl(1-(5-cyanopyridin-2-yl)piperidin-4-yl)(methyl)carbamate (430 mg, 1.36mmol) in DCM (40 mL) was added TFA (2.33 g, 20.4 mmol). The reactionmixture was stirred at 50° C. for 6 hours, then cooled to roomtemperature and concentrated in vacuo. The residue was diluted with DCM(40 mL), and then washed with 1 M NaOH aqueous solution (30 mL) followedby brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to give the title compound as lightyellow oil (265 mg, yield 100%).

MS (ESI, pos. ion) m/z: 216.9 [M+H]⁺.

Step 5)6-(4-((2,5-dichloropyrimidin-4-yl)(methyl)amino)piperidin-1-yl)nicotinonitrile

To a solution of 2,4,5-trichloropyrimidine (185 mg, 1.02 mmol) and6-(4-(methylamino)piperidin-1-yl)nicotinonitrile (265 mg, 1.224 mmol) inisopropanol (40 mL) was added triethylamine (206 mg, 2.04 mmol). Thereaction mixture was stirred at 80° C. for 2 hours then cooled to roomtemperature and concentrated in vacuo. The residue was partitionedbetween dichloromethane (50 mL) and water (30 mL). The organic layer wasseparated, washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (PE/EtOAc (v/v)=8/1) to give the titlecompound as a white solid (266 mg, yield 72%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 8.42 (d, J=2.4 Hz, 1H), 8.09 (s, 1H),7.62 (dd, J=2.1 Hz, J=9.3 Hz, 1H), 6.66 (d, J=9 Hz, 1H), 5.66-4.73 (m,1H), 4.56-4.64 (m, 2H), 3.06 (s, 3H), 3.10-3.00 (m, 2H), 1.96-1.91 (m,2H), 1.87-1.74 (m, 2H).

Step 6)6-(4-((5-chloro-2-(pyrazolo[1,5-a]pyridin-6-ylamino)pyrimidin-4-yl)(methyl) amino)piperidin-1-yl)nicotinonitrile

To a mixture of6-(4-((2,5-dichloropyrimidin-4-yl)(methyl)amino)piperidin-1-yl)nicotinonitrile(156 mg, 0.4295 mmol), pyrazolo[1,5-a]pyridin-6-amine (66.2 mg, 0.497mmol), BINAP (26.5 mg, 0.0426 mmol), Cs₂CO₃ (273.8 mg, 0.8403 mmol), andPd(OAc)₂ (11.3 mg, 0.0503 mmol) was added anhydrous 1,4-dioxane (10 mL).The reaction mixture was placed in a sealed vial then degassed andrefilled with N₂ for several times and then stirred at 150° C. under themicrowave irradiation for 1.5 h. The reaction mixture was concentratedin vacuo directly. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=100/1) to give crude product as a greensolid (120 mg). The crude product was recrystallized from MeOH (6 mL),filtered and the filter cake was washed with MeOH (3 mL). And then thefilter cake was collected and dried in vacuo to give the title compoundas a light green solid (90 mg, yield 46%).

MS (ESI, pos.ion) m/z: 460.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.29 (s, 1H), 8.42 (d, J=2.1 Hz, 1H),8.01 (s, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.61 (dd, J=9.0, 2.3 Hz, 1H), 7.46(d, J=9.3 Hz, 1H), 6.95 (dd, J=9.4, 1.6 Hz, 1H), 6.79 (s, 1H), 6.65 (d,J=9.1 Hz, 1H), 6.47 (d, J=1.9 Hz, 1H), 4.66 (ddd, J=15.9, 8.1, 4.0 Hz,1H), 4.58 (d, J=13.6 Hz, 2H), 3.12 (t, J=12.0 Hz, 2H), 3.06 (s, 3H),1.96 (d, J=10.6 Hz, 2H), 1.81 (qd, J=12.3, 4.1 Hz, 2H).

Example 26-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

Step 1) 2-chloropropanal

To a suspension of propanal (5.00 g, 86.11 mmol) in chloroform (50 mL)were added pyrrolidine-2-carboxylic acid (1.98 g, 17.24 mmol) and NCS(12.67 g, 94.82 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h,then move to room temperature and stirred overnight. To the mixture wasadded n-hexane (100 mL) and stirred further for 30 min, and thenfiltered. The filtrate was washed with water (100 mL×2), dried overanhydrous Na₂SO₄ and filtered to afford a colorless solution for 150 mL.The filtrate was used for next step without further processing.

GC-MS m/z (EI): 92.0 [M]⁺;

Step 2) 7-bromo-3-methylimidazo[1,2-a]pyridine

To the colorless solution (150 mL) obtanined from previous step wasadded 4-bromopyridin-2-amine (2.00 g, 11.57 mmol). The mixture washeated to reflux and stirred overnight, then concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/(asolution of NH₃ in MeOH (3M))(v/v)=100/1 to 50/1 to 30/1) to afford thetitle compound as brown sticky liquid (0.76 g, yield 31%).

MS (ESI, pos. ion) m/z: 211.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.79 (d, J=1.3 Hz, 1H), 7.74 (d, J=7.2Hz, 1H), 7.38 (s, 1H), 6.94 (dd, J=7.2, 1.8 Hz, 1H), 2.46 (s, 3H).

Step 3) N-(diphenylmethylene)-3-methylimidazo[1,2-a]pyridin-7-amine

To a suspension of 7-bromo-3-methylimidazo[1,2-a]pyridine (0.76 g, 3.60mmol) in anhydrous toluene (20 mL) were added Pd₂dba₃ (0.34 g, 0.37mmol), BINAP (0.47 g, 0.76 mmol), diphenylmethanimine (1.33 g, 7.33mmol) and t-BuONa (0.70 g, 7.32 mmol). The mixture was degassed andrefilled with N2 for several times and then heated to 85° C. and stirredovernight. The resulting mixture was diluted with water (40 mL), and theresulting soluion was extracted with EtOAc (50 mL×5). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound as brown liquid (1.12g, yield 100%).

MS (ESI, pos. ion) m/z: 312.0 [M+H]⁺.

Step 4) 3-methylimidazo[1,2-a]pyridin-7-amine

To a suspension ofN-(diphenylmethylene)-3-methylimidazo[1,2-a]pyridin-7-amine (1.12 g,3.60 mmol) in DCM (30 mL) was added a solution of hydrogen chloride inEtOAc (30 mL, 90 mmol, 3 M). The reaction mixture was stirred at roomtemperature overnight and then concentrated in vacuo. The residue wasdiluted with water (30 mL) and the resulting mixture was extracted withEtOAc (80 mL). The separated aqueous layer was adjusted to pH=10 withsaturated Na₂CO₃ aqueous solution, then extracted with DCM (40 mL×2) andthen a mixed solvent of DCM/MeOH (v/v)=10/1 (50 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=30/1 to 20/1to 10/1) to afford the title compound as brown liquid (0.40 g, yield76%).

MS (ESI, pos. ion) m/z: 148.2 [M+H]⁺.

Step 5) (S)—N-(1-benzylpiperidin-4-ylidene)-1-phenylethanamine

A mixture of 1-benzylpiperidin-4-one (30.06 g, 158.8 mmol) and(15)-1-phenylethanamine (28.92 g, 238.7 mmol) in toluene (300 mL) washeated to refluxed for 46 hours and removed water by Dean-Stark trap.The reaction mixture was cooled to r.t and concentrated in vacuo to givethe crude product. The crude product was used directly for the next stepwithout further purification.

Step 6) 1-benzyl-3-ethyl-N—((R)-1-phenyle thyl)piperidin-4-amine

At 10° C., to a solution of(S)—N-(1-benzylpiperidin-4-ylidene)-1-phenylethanamine (46.35 g, 158.5mmol) in THF (250 mL) was added a solution of LDA in THF (125 mL, 2 M)dropwise. The reaction was stirred at rt under N₂ atmosphere for 2hours. Then iodoethane (20.5 mL, 255 mmol) was added to the abovesolution and the reaction mixture was stirred for 2 h. After cooled downto 78° C., ethanol (250 mL) and sodium borohydride (9.62 g, 254 mmol)were added to the reaction mixture. The resulting mixture was stirred at78° C. for 15 min and then moved to 10° C. and stirred overnight. Thereaction was quenched with water (500 mL), and extracted with EtOAc (200mL×3). The combined organic layers were washed with brine (300 mL) andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/3 to 1/1 to 100% EtOAc) to afford thedesired product as yellow oil (12.50 g, yield 24.5%).

MS (ESI, pos. ion) m/z: 323.4 [M+H]⁺.

Step 7) 3-ethyl-N—((R)-1-phenylethyl)piperidin-4-amine

To a solution of 1-benzyl-3-ethyl-N—((R)-1-phenylethyl)piperidin-4-amine(12.50 g, 38.76 mmol) in 1,2-dichloroethane (200 mL) at 0° C. was added1-chloroethyl carbonochloridate (5.0 mL, 46 mmol) dropwise. The reactionmixture was stirred for 30 min, and then heated to reflux and stirredfor another 1 hour. The reaction mixture was concentrated in vacuo, andthe residue was dissolved in methanol (200 mL). The mixture was heatedto reflux and stirred overnight and concentrated in vacuo. The residuewas purified by silica gel column chromatography ((a solution of NH₃ inMeOH (3M))/DCM (v/v)=1/30 to 1/10) to afford the desired product asbrown oil (6.15 g, yield 68.3%).

MS (ESI, pos. ion) m/z: 233.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.35-7.27 (m, 4H), 7.24-7.21 (m, 1H),3.96 (q, J=6.6 Hz, 1H), 3.10-3.00 (m, 2H), 2.41 (td, J=12.3, 2.6 Hz,1H), 2.14-2.07 (m, 2H), 2.00-1.94 (m, 1H), 1.86-1.80 (m, 1H), 1.32 (d,J=6.6 Hz, 3H), 1.17-0.95 (m, 3H), 0.81 (t, J=7.5 Hz, 3H).

Step 8) tert-butyl3-ethyl-4-(((R)-1-phenylethyl)amino)piperidine-1-carboxylate

At 0° C., to a solution of3-ethyl-N-((1R)-1-phenylethyl)piperidin-4-amine (6.15 g, 26.5 mmol) indichloromethane (100 mL) were added triethylamine (9.2 mL, 66 mmol) andBoc₂O (9.1 mL, 40 mmol). The reaction mixture was stirred at roomtemperature overnight and concentrated in vacuo to afford the titlecompound as brown oil (8.80 g, yield 100%). The crude product was usedin the next step without further purification.

MS (ESI, pos. ion) m/z: 333.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.36-7.20 (m, 5H), 3.96-3.89 (m, 2H),2.68 (s, 1H), 2.06-1.97 (m, 2H), 1.79 (s, 1H), 1.44 (s, 9H), 1.33 (d,J=6.5 Hz, 3H), 1.27-0.96 (m, 5H), 0.84 (t, J=7.4 Hz, 3H).

Step 9) tert-butyl 4-amino-3-ethylpiperidine-1-carboxylate acetate

To a solution of tert-butyl3-ethyl-4-(((R)-1-phenylethyl)amino)piperidine-1-carboxylate (8.80 g,26.5 mmol) in acetic acid (100 mL) was added palladium hydroxide oncarbon (0.90 g). The reaction mixture was stirred at 70° C. under H₂atmosphere overnight. The mixture was filtered through a pad of celite,and then the filtrate was concentrated in vacuo to afford the desiredproduct as yellow oil (7.63 g, yield 100%). The crude product was usedin the next step without further purification.

MS (ESI, pos. ion) m/z: 173.2 [M-55]⁺.

Step 10) tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate

To a solution of tert-butyl 4-amino-3-ethylpiperidine-1-carboxylateacetate (6.04 g, 26.5 mmol) in ethanol (100 mL) were added2,4,5-trichloropyrimidine (4.85 g, 26.4 mmol) and triethanamine (14.7mL, 105 mmol). The reaction mixture was stirred at room temperature for12 hours and then concentrated in vacuo. The residue was purified bysilica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/8) to givethe title product as a white solid (4.80 g, yield 48.3%).

MS (ESI, pos. ion) m/z: 375.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.00 (s, 1H), 5.27 (d, J=8.7 Hz, 1H),4.31-4.10 (m, 1H), 4.10-3.98 (m, 2H), 3.00-2.84 (m, 1H), 2.56 (s, 1H),2.05-1.92 (m, 1H), 1.55-1.50 (m, 1H), 1.45 (s, 9H), 1.40-1.38 (m, 2H),1.24-1.10 (m, 1H), 0.91 (t, J=7.5 Hz, 3H).

Step 11) tert-butyl4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate

To a suspension of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(0.40 g, 1.07 mmol) in anhydrous 1,4-dioxane (10 mL) were added3-methylimidazo[1,2-a]pyridin-7-amine (0.31 g, 2.10 mmol), Pd(OAc)₂(0.049 g, 0.22 mmol), BINAP (0.14 g, 0.22 mmol) and Cs₂CO₃ (0.70 g, 2.16mmol). The reaction mixture was placed in a sealed vial then degassedand refilled with N₂ for several times and then stirred at 150° C. underthe microwave irradiation for 1 h. The mixture was concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=50/1 to 30/1 to 20/1) toafford the title compound as yellow liquid (0.40 g, yield 77%). MS (ESI,pos. ion) m/z: 485.9 [M+H]⁺.

Step 12)5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N²-(3-methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine

To a suspension of tert-butyl4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(0.41 g, 0.84 mmol) in DCM (20 mL) was added a solution of hydrogenchloride in EtOAc (20 mL, 60.0 mmol, 3.0 M). The mixture was stirred atroom temperature overnight and then concentrated in vacuo. The residuewas diluted with DCM (20 mL) and saturated Na₂CO₃ aqueous solution (20mL) and the resulting mixture was stirred for 15 min. The organic layerwas separated and the aqueous layer was extracted with DCM (30 mL×3) anda mixed solvent of DCM/MeOH (10/1 (v/v), 30 mL×3) successively. Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/a solution of NH₃ in MeOH (3M)) (v/v)=50/1 to 30/1to 20/1) to afford the title compound as a yellow solid (0.26 g, yield80%).

MS (ESI, pos. ion) m/z: 385.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.95 (d, J=1.6 Hz, 1H), 7.93 (s, 1H),7.74 (d, J=7.4 Hz, 1H), 7.30 (s, 1H), 7.07-7.02 (m, 2H), 5.12 (d, J=8.6Hz, 1H), 4.01-3.90 (m, 1H), 3.31-3.23 (m, 1H), 3.18-3.10 (m, 1H),2.88-2.78 (m, 1H), 2.52-2.46 (m, 1H), 2.44 (s, 3H), 2.20-2.12 (m, 1H),1.65-1.61 (m, 1H), 1.48-1.39 (m, 2H), 1.24-1.14 (m, 1H), 0.90 (t, J=7.5Hz, 3H).

Step 13)6-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

To a suspension of5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N²-(3-methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine(0.10 g, 0.26 mmol) in EtOH (10.0 mL) was added6-chloropyridine-3-carbonitrile (0.073 g, 0.52 mmol) and TEA (0.11 mL,0.79 mmol). The mixture was heated to reflux and stirred overnight andthen concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=50/1to 30/1) to afford the title compound as a yellow solid (87 mg, yield69%).

MS (ESI, pos. ion) m/z: 488.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.40 (d, J=2.1 Hz, 1H), 8.13 (s, 1H),7.95 (s, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.60 (dd, J=9.0, 2.3 Hz, 1H), 7.30(s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 6.64 (d, J=9.0 Hz, 1H), 5.10 (d,J=8.2 Hz, 1H), 4.64-4.52 (m, 1H), 4.44-4.34 (m, 1H), 4.28-4.16 (m, 1H),3.36-3.22 (m, 1H), 3.00-2.86 (m, 1H), 2.44 (s, 3H), 2.34-2.25 (m, 1H),1.74-1.66 (m, 1H), 1.58-1.42 (m, 2H), 1.37-1.28 (m, 1H), 1.00 (t, J=7.4Hz, 3H).

Example 36-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N²-(3-methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine(0.13 g, 0.34 mmol) in DCM (10.0 mL) were added6-chloropyridazine-3-carbonitrile (0.095 g, 0.68 mmol) and TEA (0.15 mL,1.10 mmol). The mixture was stirred at room temperature overnight, andthen concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=50/1to 30/1) to afford the title compound as a yellow solid (0.12 g, yield73%). MS (ESI, pos. ion) m/z: 489.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.20 (s, 1H), 7.95 (s, 1H), 7.76 (d,J=7.4 Hz, 1H), 7.41 (d, J=9.6 Hz, 1H), 7.29 (s, 1H), 6.95-6.83 (m, 2H),5.12 (d, J=8.1 Hz, 1H), 4.80-4.65 (m, 1H), 4.50-4.37 (m, 1H), 4.32-4.19(m, 1H), 3.48-3.33 (m, 1H), 3.09-2.95 (m, 1H), 2.50-2.30 (m, 4H),1.80-1.67 (m, 1H), 1.65-1.47 (m, 2H), 1.38-1.28 (m, 1H), 0.98 (t, J=7.1Hz, 3H).

Example 46-(4-((5-chloro-2-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) tert-butyl (1-(6-cyanopyridazin-3-yl)piperidin-4-yl)carbamate

To a solution of tert-butyl piperidin-4-yl carbamate (1.40 g, 6.99 mmol)and 6-chloropyridazine-3-carbonitrile (967.4 mg, 6.93 mmol) in EtOH (20mL) was added Et₃N (976.2 mg, 9.65 mmol). The reaction mixture wasstirred at rt overnight and then concentrated in vacuo. The residue wasstirred with a mixture of EtOH and water (10 mL/1 mL) for 0.5 hour andfiltered to give the title compound as a pale brown solid (2.13 g, yield100%).

MS (ESI, pos. ion) m/z: 304.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.83 (d, J=9.7 Hz, 1H), 7.36 (d,J=9.7 Hz, 1H), 6.89 (d, J=7.3 Hz, 1H), 4.40 (d, J=13.4 Hz, 2H),3.67-3.56 (m, 1H), 3.24-3.12 (m, 2H), 1.84 (d, J=10.1 Hz, 2H), 1.39 (s,9H), 1.35-1.31 (m, 2H).

Step 2) 6-(4-aminopiperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of tert-butyl(1-(6-cyanopyridazin-3-yl)piperidin-4-yl)carbamate (2.03 g, 6.69 mmol)in DCM (15 mL) was added a solution of HCl in EtOAc (4 M, 15 mL, 60mmol). The reaction mixture was stirred at rt for 0.5 hour andconcentrated in vacuo. The residue was dissolved in water (30 mL), andthe resulting solution was adjusted to pH=10 with a saturated Na₂CO₃aqueous solution, then extracted with DCM (250 mL×3). The combinedorganic phases were washed with brine (250 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound asan orange solid (1.20 g, yield 88.2%).

MS (ESI, pos. ion) m/z: 204.2 [M+H]⁺.

Step 3)6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of 6-(4-amino-1-piperidyl)pyridazine-3-carbonitrile(1.20 g, 5.90 mmol) and 2,4,5-trichloropyrimidine (1.50 g, 8.18 mmol) inEtOH (30 mL) was added Et₃N (1.74 g, 17.20 mmol). The reaction mixturewas stirred at rt for 4 hours, and then quenched with water (50 mL), andextracted with EtOAc (250 mL×3). The combined organic phases were washedwith brine (250 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/2) to give the title compound as anorange solid (1.06 g, yield 51.3%).

MS (ESI, pos. ion) m/z: 349.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.05 (s, 1H), 7.45 (d, J=9.6 Hz, 1H),6.89 (d, J=9.6 Hz, 1H), 5.39 (d, J=7.5 Hz, 1H), 4.56 (d, J=13.7 Hz, 2H),4.47-4.34 (m, 1H), 3.37-3.23 (m, 2H), 2.25 (dd, J=12.6, 2.8 Hz, 2H),1.60 (dd, J=12.0, 3.7 Hz, 2H).

Step 4) 7-bromoimidazo[1,2-a]pyridine

To a suspension of 4-bromopyridin-2-amine (5.26 g, 30.40 mmol) in water(50 mL) was added 2-chloroacetaldehyde (40% [w/w] in water, 15.24 g,77.66 mmol). The reaction mixture was stirred at 100° C. for 4 h, andadjusted to pH=10 with a saturated Na₂CO₃ aqueous solution, thenextracted with DCM (100 mL×3). The combined organic phases were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/100) to give the title compound asyellow oil (5.93 g, yield 100%).

MS (ESI, pos. ion) m/z: 197.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.00 (d, J=7.2 Hz, 1H), 7.82 (d, J=0.8Hz, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 6.90 (dd, J=7.2, 1.7 Hz, 1H).

Step 5) N-(diphenylmethylene)imidazo[1,2-a]pyridin-7-amine

To a solution of 7-bromoimidazo[1,2-a]pyridine (5.50 g, 27.91 mmol) anddiphenylmethanimine (10.00 g, 55.19 mmol) in toluene (200 mL) were addedPd₂(dba)₃ (97%, 1.30 g, 1.38 mmol), BINAP (1.70 g, 2.73 mmol) andt-BuONa (5.40 g, 56.19 mmol). The reaction mixture was stirred at 100°C. for 2 hours and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as brown oil (8.00 g, yield 96%).

MS (ESI, pos. ion) m/z: 298.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.84 (d, J=7.1 Hz, 1H), 7.75 (d, J=7.4Hz, 2H), 7.51-7.45 (m, 2H), 7.43-7.38 (m, 3H), 7.31-7.22 (m, 3H),7.18-7.15 (m, 2H), 6.88 (d, J=0.8 Hz, 1H), 6.30 (dd, J=7.1, 1.9 Hz, 1H).

Step 6) imidazo[1,2-a]pyridin-7-amine

To a solution of N-(diphenylmethylene)imidazo[1,2-a]pyridin-7-amine(8.00 g, 26.9 mmol) in DCM (25 mL) was added a solution of HCl in EtOAc(50 mL, 150 mmol, 3 M). The reaction mixture was stirred at rt overnightand concentrated in vacuo. The residue was dissolved in water (50 mL),and the resulting solution was adjusted to pH=10 with a saturated Na₂CO₃aqueous solution, and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the titlecompound as a brown solid (2.93 g, yield 82%).

MS (ESI, pos. ion) m/z: 134.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.74 (d, J=7.2 Hz, 1H), 7.31 (d, J=1.0Hz, 1H), 7.23 (s, 1H), 6.61-6.56 (m, 1H), 6.21 (dd, J=7.2, 2.2 Hz, 1H),4.19 (s, 2H).

Step 7)6-(4-((5-chloro-2-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(110.0 mg, 0.31 mmol) and imidazo[1,2-a]pyridin-7-amine (62.0 mg, 0.47mmol) in 1,4-dioxane (25 mL) were added Pd(OAc)₂ (25.0 mg, 0.11 mmol),BINAP (52.3 mg, 0.08 mmol) and Cs₂CO₃ (213.8 mg, 0.66 mmol). Thereaction mixture was stirred at 120° C. overnight and concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/30) to give the title compound as a beige solid (109.4mg, yield 77.9%).

MS (ESI, pos. ion) m/z: 446.8 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.23 (s, 1H), 8.00 (d, J=7.3 Hz, 1H),7.97 (s, 1H), 7.53 (s, 1H), 7.46-7.43 (m, 2H), 7.05 (s, 1H), 6.90 (d,J=9.6 Hz, 1H), 6.76 (dd, J=7.3, 1.4 Hz, 1H), 5.24 (d, J=7.0 Hz, 1H),4.57 (d, J=13.1 Hz, 2H), 4.49-4.37 (m, 1H), 3.54-3.44 (m, 2H), 2.36 (dd,J=12.5, 2.7 Hz, 1H), 1.73-1.50 (m, 2H).

Example 56-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-7-ylamino)-5-chloropyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

Step 1) N-(diphenylmethylene)-[1,2,4]triazolo[4,3-a]pyridin-7-amine

To a suspension of 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (930.9 mg,4.70 mmol) and diphenylmethanimine (1.70 g, 9.38 mmol) in toluene (40mL) were added Pd₂(dba)₃ (217.7 mg, 0.24 mmol), BINAP (293.4 mg, 0.45mmol) and t-BuONa (908.4 mg, 9.45 mmol). The reaction mixture wasstirred at 100° C. overnight and quenched with water (50 mL), and theresulting mixture was extracted with EtOAc (100 mL×3). The combinedorganic phases were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as a brown solid (1.66 g, yield 46.3%).

MS (ESI, pos. ion) m/z: 299.2 [M+H]⁺.

Step 2) [1,2,4]triazolo[4,3-a]pyridin-7-amine

To a solution ofN-(diphenylmethylene)-[1,2,4]triazolo[4,3-a]pyridin-7-amine (942.8 mg,3.16 mmol) in 1,4-dioxane (30 mL) was added a solution of HCl in water(30 mL, 120 mmol, 4 M) dropwise. The reaction mixture was stirred at rtovernight and adjusted to pH=10 with a saturated Na₂CO₃ aqueoussolution, then the resulting mixture was extracted with DCM (250 mL×6).The combined organic phases were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/10) to give the title compound as ayellow solid (162.0 mg, yield 38.2%).

MS (ESI, pos. ion) m/z: 135.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.46 (d, J=14.8 Hz, 1H), 7.82 (dd,J=14.5, 7.3 Hz, 1H), 6.52-6.43 (m, 1H), 6.41-6.30 (m, 1H).

Step 3) tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-7-ylamino)-5-chloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate

To a suspension of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(431.2 mg, 1.15 mmol) and [1,2,4]triazolo[4,3-a]pyridin-7-amine (148.6mg, 1.11 mmol) in 1,4-dioxane (15 mL) were added Pd(OAc)₂ (65.6 mg, 0.29mmol), BINAP (190.6 mg, 0.29 mmol) and Cs₂CO₃ (759.7 mg, 2.33 mmol). Thereaction mixture was placed in a sealed vial then degassed and refilledwith N₂ for several times and then, stirred at 150° C. under themicrowave irradiation for 2 h. The resulting mixture was concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/20) to give the title compound as a yellow solid(210.8 mg, yield 38.8%).

MS (ESI, pos. ion) m/z: 472.9 [M+H]⁺.

Step 4)N²-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-5-chloro-N⁴-(3-ethylpiperidin-4-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-7-ylamino)-5-chloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(201.9 mg, 0.43 mmol) in DCM (10 mL) was added a solution of HCl inEtOAc (10 mL, 40 mmol, 4 M). The reaction mixture was stirred at rt for0.5 hour and then concentrated in vacuo. The residue was dissolved inwater (30 mL) and adjusted to pH=10 with a saturated Na₂CO₃ aqueoussolution, then extracted with DCM (250 mL×3). The combined organicphases were washed with brine (250 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (MeOH/DCM (v/v)=1/5) to give the titlecompound as a beige solid (91.8 mg, yield 57.7%).

MS (ESI, pos. ion) m/z: 372.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃+CD₃OD) δ (ppm): 8.65 (s, 1H), 8.38 (s, 1H), 8.00(d, J=7.4 Hz, 1H), 7.84 (s, 1H), 6.79 (dd, J=7.4, 1.8 Hz, 1H), 4.11-4.04(td, J=11.1, 4.3 Hz, 1H), 3.28-3.26 (m, 2H), 3.15 (td, J=13.0, 3.2 Hz,2H), 2.87 (t, J=12.5 Hz, 1H), 2.25-1.99 (m, 4H), 1.67-1.61 (m, 1H), 0.82(t, J=7.5 Hz, 3H).

Step 5)6-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-7-ylamino)-5-chloropyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

To a suspension ofN²-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-5-chloro-N⁴-(3-ethylpiperidin-4-yl)pyrimidine-2,4-diamine(37.9 mg, 0.102 mmol) and 6-chloronicotinonitrile (29.0 mg, 0.209 mmol)in EtOH (10 mL) was added Et₃N (33.8 mg, 0.334 mmol). The reactionmixture was stirred at reflux overnight and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as a beige solid (28.6 mg, yield59.2%).

MS (ESI, pos. ion) m/z: 474.8 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.68 (s, 1H), 8.45 (s, 1H), 8.42 (d,J=1.9 Hz, 1H), 8.00-7.99 (m, 2H), 7.62 (dd, J=9.0, 2.2 Hz, 1H), 7.32 (s,1H), 6.80 (d, J=6.9 Hz, 1H), 6.66 (d, J=9.0 Hz, 1H), 5.19 (d, J=8.4 Hz,1H), 4.65 (d, J=13.1 Hz, 1H), 4.43 (d, J=13.5 Hz, 1H), 4.21 (qd, J=10.6,4.2 Hz, 1H), 3.38-3.31 (m, 1H), 2.92 (dd, J=13.6, 10.9 Hz, 1H),2.35-2.29 (m, 1H), 1.77-1.71 (m, 1H), 1.41 (t, J=7.3 Hz, 1H), 1.39-1.30(m, 2H), 1.02 (t, J=7.5 Hz, 3H).

Example 66-(4-((5-chloro-2-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

Step 1) tert-butyl4-((5-chloro-2-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate

A mixture of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(202.4 mg, 0.5393 mmol), imidazo[1,2-a]pyridin-7-amine (91.4 mg, 0.686mmol), BINAP (32.8 mg, 0.0527 mmol), Cs₂CO₃ (351.4 mg, 1.079 mmol),Pd(OAc)₂ (12.3 mg, 0.0548 mmol) and 1,4-dioxane (25 mL) was placed in asealed tube. The reaction mixture was heated to 150° C. and stirred for4 h. The reaction mixture was concentrated in vacuo, and the residue wasdiluted with water (50 mL), the resulting mixture was extracted with amixed solvent of DCM/MeOH (10/1 (v/v), 80 mL×4). The organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) togive the title compound as a light yellow solid (105 mg, yield 41%).

MS (ESI, pos.ion) m/z: 471.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02-7.97 (m, 2H), 7.95 (s, 1H), 7.54(s, 1H), 7.45 (s, 1H), 6.95 (d, J=6.9 Hz, 1H), 5.11 (d, J=8.6 Hz, 1H),4.09 (d, J=14.9 Hz, 3H), 3.03 (s, 1H), 2.13 (dd, J=12.9, 3.4 Hz, 1H),1.78-1.55 (m, 6H), 1.48 (s, 9H), 0.94 (t, J=7.5 Hz, 3H).

Step 2)5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N²-(imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine

tert-butyl4-((5-chloro-2-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(105 mg, 0.2225 mmol) was dissolved in a solution of hydrogen chloridein EtOAc (16 mL, 24 mmol, 1.5 M). The reaction mixture was stirred at rtfor 4 h, and then concentrated in vacuo. The residue was diluted withsaturated Na₂CO₃ aqueous solution (20 mL) and the resulting mixture wasextracted with a mixed solvent of DCM/MeOH (10/1 (v/v), 50 mL×4). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by preparative TLC togive the title compound as a light yellow solid (70 mg, yield 85%).

Step 3)6-(4-((5-chloro-2-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

To a solution of5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N²-(imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine(70 mg, 0.1882 mmol) in EtOH (10 mL) were added6-chloropyridine-3-carbonitrile (33.8 mg, 0.244 mmol) and DIPEA (92.4mg, 0.715 mmol). The reaction was heated to reflux and stirredovernight. The resulting mixture was concentrated in vacuo, and theresidue was purified by preparative TLC (DCM/MeOH (v/v)=10/1) to givethe title compound as a light yellow solid (32 mg, yield 36%).

MS (ESI, pos.ion) m/z: 474.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.40 (d, J=2.0 Hz, 1H), 8.32 (s, 1H),8.04 (d, J=7.4 Hz, 1H), 7.96 (s, 1H), 7.67 (s, 1H), 7.59 (dd, J=9.0, 2.2Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.46 (s, 1H), 7.16 (d, J=6.3 Hz, 1H),6.64 (d, J=9.1 Hz, 1H), 5.15 (d, J=8.5 Hz, 1H), 4.57 (d, J=12.8 Hz, 1H),4.39 (d, J=13.5 Hz, 1H), 4.26 (ddd, J=19.2, 10.5, 4.2 Hz, 1H), 3.38 (t,J=11.7 Hz, 1H), 3.10-3.01 (m, 1H), 2.31 (d, J=9.4 Hz, 1H), 1.72 (ddd,J=14.0, 7.4, 3.1 Hz, 1H), 1.47 (ddd, J=15.9, 15.0, 6.2 Hz, 2H),1.39-1.30 (m, 1H), 1.00 (t, J=7.5 Hz, 3H).

Example 76-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-7-ylamino)-5-chloropyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)pyridazine-3-carbonitrile

To a suspension ofN²-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-5-chloro-N⁴-(3-ethylpiperidin-4-yl)pyrimidine-2,4-diamine(35.8 mg, 0.096 mmol) and 6-chloropyridazine-3-carbonitrile (27.6 mg,0.198 mmol) in EtOH (10 mL) was added Et₃N (46.0 mg, 0.455 mmol). Thereaction mixture was stirred at rt overnight and concentrated in vacuo.The residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as a beige solid (39.5 mg, yield86.5%).

MS (ESI, pos. ion) m/z: 475.8 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.69 (s, 1H), 8.49 (s, 1H), 8.01 (d,J=6.5 Hz, 1H), 8.00 (s, 1H), 7.45 (d, J=9.6 Hz, 1H), 7.23 (s, 1H), 6.91(d, J=9.6 Hz, 1H), 6.79 (dd, J=7.3, 1.5 Hz, 1H), 5.22 (d, J=8.3 Hz, 1H),4.84 (d, J=11.7 Hz, 1H), 4.46 (d, J=13.2 Hz, 1H), 4.32-4.19 (m, 1H),3.55-3.43 (m, 2H), 2.41 (dd, J=13.2, 3.3 Hz, 1H), 1.82-1.72 (m, 1H),1.59-1.52 (m, 2H), 1.37-1.33 (m, 1H), 1.02 (t, J=7.5 Hz, 3H).

Example 86-(4-((5-chloro-2-((2-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidin-1-yl)pyridazine-3-carbonitrile

Step 1) tert-butyl 4-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-3-ethylpiperidine-1-carboxylate

To a solution of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(1.31 g, 3.49 mmol) in tetrahydrofuran (30 mL) at 0° C. was added sodiumhydride (60% suspended in mineral oil, 98.6 mg, 2.47 mmol) and themixture was stirred at 0° C. for 30 min. Iodomethane (0.2 mL, 3 mmol)was added to the above solution dropwise. The resulting mixture wasmoved to room temperature and stirred for 8 hours. The reaction wasquenched with water (50 mL), and extracted with EtOAc (100 mL×3). Thecombined organic layers were concentrated in vacuo, and the residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) togive the desired product as a white solid (662.3 mg, yield 48.7%).

MS (ESI, pos. ion) m/z: 389.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.05 (s, 1H), 4.36-4.29 (m, 2H), 3.04(s, 3H), 2.86-2.79 (m, 1H), 2.42-2.36 (m, 1H), 1.86-1.83 (m, 1H),1.78-1.63 (m, 2H), 1.48 (s, 9H), 1.45-1.38 (m, 1H), 1.27-1.24 (m, 1H),1.03-0.93 (m, 1H), 0.89 (t, J=7.3 Hz, 3H).

Step 2) 7-bromo-2-methylimidazo[1,2-a]pyridine

To a solution of 4-bromopyridin-2-amine (1.08 g, 6.24 mmol) in H₂O (20mL) were added 1-bromo-2,2-dimethoxypropane (5.59 g, 30.5 mmol) and4-methylbenzenesulfonic acid (209.4 mg, 1.216 mmol). The reactionmixture was heated to reflux and stirred for 12 hours and then adjustedto pH=10 with saturated Na₂CO₃ aqueous solution, the resulting mixturewas extracted with EtOAc (100 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography(PE/EtOAc(v/v)=3/1) to give the title compound as a yellow solid (750mg, yield 57%).

MS (ESI, pos. ion) m/z: 211.1 [M+H]⁺.

Step 3) N-(diphenylmethylene)-2-methylimidazo[1,2-a]pyridin-7-amine

A mixture of 7-bromo-2-methyl-imidazo[1,2-a]pyridine (750 mg, 3.5535mmol), Pd₂(dba)₃ (304.6 mg, 0.3326 mmol), BINAP (216.7 mg, 0.3480 mmol),t-BuONa (703.5 mg, 7.320 mmol) and diphenylmethanimine (1.30 g, 7.17mmol) was dissolved in toluene (20 mL). The reaction mixture was stirredat 80° C. overnight and then diluted with water (80 mL). The resultingmixture was extracted with EtOAc (100 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography(DCM/MeOH(v/v)=100/1) to give the title compound as a yellow solid (580mg, yield 52.4%).

MS (ESI, pos. ion) m/z: 311.95 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77-7.71 (m, 3H), 7.49 (t, J=7.3 Hz,1H), 7.41 (t, J=7.5 Hz, 2H), 7.32-7.23 (m, 3H), 7.19-7.11 (m, 3H), 6.79(d, J=1.1 Hz, 1H), 6.23 (dd, J=7.1, 1.9 Hz, 1H), 2.37 (s, 3H).

Step 4) 2-methylimidazo[1,2-a]pyridin-7-amine

A mixture of N-(diphenylmethylene)-2-methylimidazo[1,2-a]pyridin-7-amine(580 mg, 1.863 mmol) in a solution of hydrogen chloride in EtOAc (20 mL,30 mmol, 1.5 M) was stirred at rt for 7 hours and then washed with water(50 mL×2). The combined aqueous layers were adjusted to pH=10 withsaturated Na₂CO₃ aqueous solution, and the resulting mixture wasextracted with a mixed solvent of DCM/MeOH (10/1 (v/v), 150 mL×4). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH3 in MeOH (7M)) (v/v)=40/1) to givethe title compound as a light yellow solid (90 mg, yield 33%). MS (ESI,pos.ion) m/z: 148.20 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.73 (d, J=7.2 Hz, 1H), 7.05 (s, 1H),6.56 (d, J=1.6 Hz, 1H), 6.19 (dd, J=7.2, 2.2 Hz, 1H), 3.91 (s, 2H), 2.34(s, 3H).

Step 5) tert-butyl4-((5-chloro-2-((2-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidine-1-carboxylate

A mixture of tert-butyl4-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-3-ethylpiperidine-1-carboxylate(208 mg, 0.5343 mmol), 2-methylimidazo[1,2-a]pyridin-7-amine (70 mg,0.47561 mmol), Pd(OAc)₂ (11.5 mg, 0.0512 mmol), BINAP (28.6 mg, 0.0459mmol) and Cs₂CO₃ (316.7 mg, 0.9720 mmol) was dissolved in 1,4-dioxane(15 mL). The reaction mixture was heated to reflux and stirred overnightand then concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH(v/v)=40/1) to give the title compound asa yellow solid (140 mg, yield 58%).

MS (ESI, pos. ion) m/z: 500.3 [M+H]⁺.

Step 6)5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N⁴-methyl-N²-(2-methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine

A mixture of tert-butyl4-((5-chloro-2-((2-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidine-1-carboxylate(140 mg, 0.2800 mmol) in a solution of hydrogen chloride in EtOAc (20mL, 60 mmol, 3 M) was stirred at rt for 1 hour and concentrated invacuo. The residue was diluted with saturated Na₂CO₃ (40 mL) aqueoussolution and the resulting mixture was extracted with a mixed solvent ofDCM/MeOH (10/1 (v/v), 50 mL×6). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by a preparative TLC (DCM/(a solution of NH₃ in MeOH (7M))(v/v)=10/1) to give the title compound as a light yellow solid (105 mg,yield 93%).

MS (ESI, pos.ion) m/z: 400.0 [M+H]⁺.

Step 7)6-(4-((5-chloro-2-((2-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidin-1-yl)pyridazine-3-carbonitrile

To a solution of5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N⁴-methyl-N²-(2-methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine(105 mg, 0.2626 mmol) and 6-chloropyridazine-3-carbonitrile (44.6 mg,0.320 mmol) in ethanol (10 mL) was added TEA (96.8 mg, 0.957 mmol). Thereaction was stirred at rt overnight and concentrated in vacuo. Theresidue was purified by preparative TLC (DCM/MeOH (v/v)=10/1) to givethe title compound as a light yellow solid (38 mg, yield 28.8%).

MS (ESI, pos.ion) m/z: 503.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.22 (s, 1H), 7.97 (s, 1H), 7.91 (t,J=9.3 Hz, 2H), 7.44 (d, J=9.6 Hz, 1H), 7.19 (s, 1H), 7.12 (d, J=6.6 Hz,1H), 6.91 (d, J=9.7 Hz, 1H), 4.79 (d, J=12.3 Hz, 1H), 4.64 (d, J=13.8Hz, 1H), 4.52 (td, J=11.4, 3.9 Hz, 1H), 3.29 (t, J=12.0 Hz, 1H), 3.07(s, 3H), 2.86-2.77 (m, 1H), 2.47 (s, 3H), 2.14 (d, J=10.1 Hz, 1H),1.93-1.76 (m, 2H), 1.59-1.50 (m, 1H), 1.15-1.05 (m, 1H), 0.94 (t, J=7.5Hz, 3H).

Example 96-(4-((2-([1,2,4]triazolo[1,5-a]pyridin-6-ylamino)-5-chloropyrimidin-4-yl)(methyl)amino)piperidin-1-yl)nicotinonitrile

Step 1) N-(diphenylmethylene)-[1,2,4]triazolo[1,5-a]pyridin-6-amine

To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (700 mg, 3.5350mmol), diphenylmethanimine (1.28 g, 7.06 mmol) and t-BuONa (680 mg,7.076 mmol) in toluene (50 mL) were added BINAP (221 mg, 0.3549 mmol)and Pd₂(dba)₃ (167 mg, 0.1769 mmol). The mixture was degassed for 5 minand refilled with N₂ and then stirred at 100° C. for 4 h. The reactionwas quenched with water (100 mL), and extracted with EtOAc (100 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=5/1 to 1/1) to give the title compound asa yellow solid (1.01 g, 95.8%).

MS (ESI, pos. ion) m/z: 299.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.21 (s, 1H), 8.04 (d, J=1.2 Hz, 1H),7.79-7.73 (m, 2H), 7.50 (dd, J=8.4, 2.9 Hz, 2H), 7.42 (t, J=7.5 Hz, 2H),7.31 (t, J=6.2 Hz, 3H), 7.14 (dd, J=7.7, 1.7 Hz, 2H), 7.03 (dd, J=9.4,2.0 Hz, 1H).

Step 2) [1,2,4]triazolo[1,5-a]pyridin-6-amine

To a solution ofN-(diphenylmethylene)-[1,2,4]triazolo[1,5-a]pyridin-6-amine (1.01 g,3.39 mmol) in DCM (15 mL) was added a solution of hydrogen chloride inEtOAc (16 mL, 48 mmol, 3 M). The reaction mixture was stirred at rt for4 hours and concentrated in vacuo. The residue was dissolved in water(15 mL) and adjusted to pH=10 with a saturated NaHCO₃ aqueous solution,then the resulting mixture was concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=50/1 to20/1) to give the title compound as a yellow solid (430 mg, yield94.7%).

MS (ESI, pos. ion) m/z: 135.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.17 (s, 1H), 8.02 (d, J=1.4 Hz, 1H),7.56 (d, J=9.4 Hz, 1H), 7.19 (dd, J=9.4, 2.0 Hz, 1H), 5.24 (s, 2H).

Step 3)6-(4-((2-([1,2,4]triazolo[1,5-a]pyridin-6-ylamino)-5-chloropyrimidin-4-yl)(methyl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)(methyl)amino)piperidin-1-yl)nicotinonitrile(500 mg, 1.377 mmol), [1,2,4]triazolo[1,5-a]pyridin-6-amine (222 mg,1.6550 mmol) and Cs₂CO₃ (1.35 g, 4.14 mmol) in 1,4-dioxane (10 mL) wasadded Pd(OAc)₂ (62 mg, 0.2762 mmol) and BINAP (171.5 mg, 0.2754 mmol).The reaction mixture was placed in a sealed vial then degassed andrefilled with N₂ for several times and then, stirred at 150° C. underthe microwave irradiation for 2 hours. The mixture was concentrate invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=5/1 to 1/1) and further purified by preparative TLC(DCM/MeOH (v/v)=10/1) successively to give the title compound as a lightyellow solid (566 mg, yield 89.2%).

MS (ESI, pos. ion) m/z: 461.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.53 (d, J=1.5 Hz, 1H), 8.42 (d, J=2.2Hz, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.62 (dd,J=9.0, 2.3 Hz, 1H), 7.33 (dd, J=9.5, 2.0 Hz, 1H), 7.08 (s, 1H), 6.66 (d,J=9.1 Hz, 1H), 4.68 (ddd, J=11.9, 7.9, 3.9 Hz, 1H), 4.61 (d, J=14.1 Hz,2H), 3.13 (t, J=11.9 Hz, 2H), 3.07 (s, 3H), 1.98 (d, J=10.2 Hz, 2H),1.84 (qd, J=12.3, 4.1 Hz, 2H).

Example 106-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

Step 1) tert-butyl4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidine-1-carboxylate

To a solution of tert-butyl4-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-3-ethylpiperidine-1-carboxylate(450 mg, 1.16 mmol) and 3-methylimidazo[1,2-a]pyridin-7-amine (200 mg,1.36 mmol) in 1,4-dioxane (8 mL) were added Pd(OAc)₂ (51 mg, 0.227mmol), BINAP (141 mg, 0.226 mmol) and Cs₂CO₃ (735 mg, 2.56 mmol). Thereaction mixture was placed in a sealed vial then degassed and refilledwith N₂ for several times and then, stirred at 150° C. under themicrowave irradiation for 1 h. The resulting mixture was cooled down tort and filtered. The filter cake was washed with DCM (20 mL×2) and thefiltrate was concentrated in vacuo. The residue was purified by silicagel column chromatography ((a solution of NH₃ in MeOH(7M))/DCM(v/v)=1/50) to give the title compound as orange yellow oil(390 mg, yield 67.5%).

MS (ESI, pos. ion) m/z: 500.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.21 (s, 1H), 7.96 (s, 2H), 7.80 (d,J=6.7 Hz, 1H), 7.28 (s, 1H), 4.27 (d, J=9.0 Hz, 2H), 3.05 (s, 3H), 2.86(s, 1H), 2.61 (s, 4H), 2.43 (s, 2H), 1.91-1.88 (m, 1H), 1.78-1.63 (m,3H), 1.48 (s, 9H), 1.41 (t, J=6.2 Hz, 1H), 0.88-0.86 (m, 3H).

Step 2)5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N⁴-methyl-N²-(3-methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidine-1-carboxylate (391 mg,0.782 mmol) in dichloromethane (20 mL) was added a solution of hydrogenchloride in EtOAc (10 mL, 30 mmol, 3 M). The reaction mixture wasstirred at rt overnight and concentrated in vacuo. The residue wasdissolved in EtOAc (20 mL) and the resulting mixture was adjusted toPh=10 with a saturated NaHCO₃ aqueous solution, then extracted withEtOAc (50 mL×3). The combined organic phases were washed with brine (50mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give the title compound as a yellow solid (300 mg, yield 87.9%).

MS (ESI, pos. ion) m/z: 200.8 [(M+H)/2]⁺.

Step 3)6-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

To a solution of5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N⁴-methyl-N²-(3-methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine(101 mg, 0.253 mmol) and 6-chloronicotinonitrile (52 mg, 0.375 mmol) inethanol (20 mL) was added TEA (78 mg, 0.771 mmol). The mixture wasstirred at 80° C. for 8 hours and concentrated in vacuo. The residue waspurified by preparative TLC (MeOH/DCM (v/v)=1/10) to afford the titlecompound as a yellow solid (40 mg, yield 31.6%).

MS (ESI, pos. ion) m/z: 502.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.94 (s, 1H), 8.49 (d, J=1.9 Hz, 1H),8.31-8.23 (m, 2H), 8.15 (s, 1H), 7.86-7.83 (m, 1H), 7.37 (s, 1H), 7.29(s, 1H), 7.01 (d, J=9.1 Hz, 1H), 4.69-4.59 (m, 2H), 4.41 (s, 1H), 2.97(s, 3H), 2.72 (t, J=12.3 Hz, 1H), 2.42 (s, 3H), 1.95 (d, J=11.7 Hz, 1H),1.82-1.75 (m, 2H), 1.43 (s, 1H), 1.05 (s, 1H), 0.87 (t, J=7.3 Hz, 3H).

Example 116-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-ethylpiperidin-1-yl)pyridazine-3-carbonitrile

To a solution of5-chloro-N⁴-(3-ethylpiperidin-4-yl)-N⁴-methyl-N²-(3-methylimidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine(100 mg, 0.250 mmol) and 6-chloropyridazine-3-carbonitrile (53 mg, 0.380mmol) in ethanol (20 mL) was added TEA (78 mg, 0.771 mmol). The mixturewas stirred at rt overnight and concentrated in vacuo. The residue waspurified by preparative TLC (MeOH/DCM (v/v)=1/20) to afford the titlecompound as a yellow solid (86 mg, yield 68%).

MS (ESI, pos. ion) m/z: 503.4 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.91 (s, 1H), 8.29-8.23 (m, 2H), 8.15(s, 1H), 7.84 (d, J=9.7 Hz, 1H), 7.41 (d, J=9.8 Hz, 1H), 7.35 (s, 1H),7.28 (s, 1H), 4.71 (d, J=26.9 Hz, 2H), 4.44 (s, 1H), 3.26 (s, 2H), 2.97(s, 3H), 2.42 (s, 3H), 1.98 (d, J=11.6 Hz, 1H), 1.93-1.74 (m, 2H), 1.43(s, 1H), 1.06 (s, 1H), 0.87 (t, J=7.2 Hz, 3H).

Example 126-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(100.4 mg, 0.29 mmol) and 3-methylimidazo[1,2-a]pyridin-7-amine (64.2mg, 0.44 mmol) in 1,4-dioxane (8 mL) were added Pd(OAc)₂ (6.8 mg, 0.03mmol), BINAP (18.0 mg, 0.03 mmol) and Cs₂CO₃ (281.5 mg, 0.86 mmol). Themixture was stirred at 100° C. under N₂ atmosphere for 2 hours and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/40 to 1/20) to afford the targetproduct as a white solid (83.4 mg, yield 63.1%).

MS (ESI, pos. ion) m/z: 461.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.56 (s, 1H), 8.22 (s, 1H), 8.12 (d,J=7.4 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.46 (d, J=9.8 Hz,1H), 7.17 (s, 1H), 7.12 (dd, J=7.4, 1.9 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H),4.68-4.65 (m, 2H), 4.44-4.37 (m, 1H), 3.28-3.21 (m, 2H), 2.40 (s, 3H),2.10-2.07 (m, 2H), 1.74-1.63 (m, 2H).

Example 136-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 2-chloropropanal

To a suspension of propanal (20.00 g, 344.4 mmol) in chloroform (200 mL)were added pyrrolidine-2-carboxylic acid (7.93 g, 68.9 mmol) and NCS(50.58 g, 378.8 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h,then move to room temperature and stirred overnight. To the mixture wasadded n-hexane (400 mL) and stirred for 30 min, and then filtered. Thefiltrate was washed with water (200 mL×2), dried over anhydrous Na₂SO₄,and filtered to afford a colorless solution for 600 mL (0.57 mol/L,yield 100%). The filtrate was used for next step without furtherprocessing.

GC-MS m/z (EI): 92.0 [M]⁺.

Step 2) 6-bromo-3-methylimidazo[1,2-a]pyridine

To the colorless solution (120 mL, 0.57 mol/L, 68.40 mmol) obtained fromprevious step was added 5-bromopyridin-2-amine (3.00 g, 17.36 mmol). Themixture was heated to reflux and stirred for 20 hours, and thenconcentrated in vacuo. The residue was diluted with DCM (50 mL) andsaturated Na₂CO₃ aqueous solution (50 mL), the resulting mixture wasstirred for 30 min. The organic layer was separated and the aqueouslayer was extracted with DCM (100 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (DCM (100%)to DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=200/1 to 100/1) to affordthe title compound as a brown solid (1.50 g, yield 41%).

MS (ESI, pos. ion) m/z: 211.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02 (s, 1H), 7.50 (d, J=9.5 Hz, 1H),7.41 (s, 1H), 7.21 (dd, J=9.5, 1.7 Hz, 1H), 2.47 (s, 3H).

Step 3) N-(diphenylmethylene)-3-methylimidazo[1,2-a]pyridin-6-amine

To a suspension of 6-bromo-3-methyl-imidazo[1,2-a]pyridine (1.50 g, 7.11mmol) in anhydrous toluene (35 mL) were added Pd₂(dba)₃ (0.65 g, 0.71mmol), BINAP (0.89 g, 1.43 mmol), t-BuONa (1.38 g, 14.32 mmol) anddiphenylmethanimine (2.58 g, 14.2 mmol). The mixture was degassed andrefilled with N₂ for several times and then heated to 85° C. and stirredovernight. The resulting mixture was filtered and the filter cake waswashed with EtOAc (100 mL). The filtrate was washed with water (50mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto afford the title compound as brown liquid (2.21 g, yield 100%).

MS (ESI, pos. ion) m/z: 312.3 [M+H]⁺.

Step 4) 3-methylimidazo[1,2-a]pyridin-6-amine

To a suspension ofN-(diphenylmethylene)-3-methylimidazo[1,2-a]pyridin-6-amine (2.21 g,7.10 mmol) in DCM (50.0 mL) was added a solution of hydrogen chloride inEtOAc (50 mL, 150 mmol, 3 M). The mixture was stirred at roomtemperature for 3 hours and then concentrated in vacuo. The residue wasdiluted with water (50 mL) and the resulting mixture was extracted withEtOAc (50 mL×2). The aqueous layer was adjusted to pH=10 with asaturated Na₂CO₃ aqueous solution, then extracted with DCM (100 mL×3)and a mixed solvent of DCM/MeOH (10/1 (v/v), 100 mL×3) successively. Thecombined organic layers was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=50/1 to 30/1to 10/1) to afford the title compound as a dark green solid (0.45 g,yield 43%).

MS (ESI, pos. ion) m/z: 148.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.44 (d, J=9.4 Hz, 1H), 7.33-7.28 (m,2H), 6.76 (dd, J=9.4, 2.1 Hz, 1H), 3.46 (s, 2H), 2.38 (s, 3H).

Step 5)6-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(70 mg, 0.20 mmol) in anhydrous 1,4-dioxane (5.0 mL) were added3-methylimidazo[1,2-a]pyridin-6-amine (46 mg, 0.31 mmol), Pd(OAc)₂ (6mg, 0.028 mmol), BINAP (16 mg, 0.025 mmol) and Cs₂CO₃ (0.20 g, 0.61mmol). The mixture was degassed and refilled with N₂ for several timesand then heated to reflux and stirred for 3 hours. The resulting mixturewas concentrated in vacuo and the residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=40/1 to 20/1) to afford the crudeproduct as a brown solid. The crude product was stirred with EtOAc (2mL) at rt for 30 min, then filtered. The solid was dried in vacuo toafford the title compound as a light green solid (25 mg, yield 27%).

MS (ESI, pos. ion) m/z: 461.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.54 (s, 1H), 7.89 (s, 1H), 7.47 (d,J=9.7 Hz, 1H), 7.44 (d, J=9.7 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J=9.3 Hz,1H), 6.90 (d, J=9.6 Hz, 1H), 4.46-4.38 (m, 2H), 4.29-4.21 (m, 1H),3.26-3.17 (m, 2H), 2.44 (s, 3H), 2.20-2.14 (m, 2H), 1.61-1.53 (m, 2H).

Example 146-(4-((5-chloro-2-((3-cyclopropylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 7-bromo-3-iodoimidazo[1,2-a]pyridine

To a solution of 7-bromoimidazo[1,2-a]pyridine (5.93 g, 30.1 mmol) inDMF (60 mL) was added NIS (9.19 g, 40.8 mmol). The reaction mixture wasstirred at 100° C. for 1 hour, then cooled down to rt and quenched withwater (50 mL), then extracted with DCM (100 mL×3). The combined organicphases were washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc/PE (v/v)=1/10) to give the titlecompound as a yellow solid (8.45 g, yield 86.9%).

MS (ESI, pos. ion) m/z: 323.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02 (d, J=7.3 Hz, 1H), 7.83 (d, J=1.2Hz, 1H), 7.69 (s, 1H), 7.05 (dd, J=7.3, 1.7 Hz, 1H).

Step 2) 7-bromo-3-cyclopropylimidazo[1,2-a]pyridine

To a suspension of 7-bromo-3-iodoimidazo[1,2-a]pyridine (7.04 g, 21.80mmol) and potassium cyclopropyltrifluoroborate (3.87 g, 26.20 mmol) in amixture of toluene (100 mL) and water (10 mL) were added Pd(OAc)₂ (493.4mg, 2.20 mmol), butyldi-1-adamantylphosphine (1.17 g, 3.26 mmol) andCs₂CO₃ (21.31 g, 65.40 mmol). The reaction mixture was stirred at 110°C. overnight, then cooled down to rt and quenched with water (50 mL).The resulting mixture was extracted with DCM (250 mL×3). The combinedorganic phases were washed with brine (250 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the titlecompound as a pale yellow solid (2.57 g, yield 49.7%).

MS (ESI, pos. ion) m/z: 237.2 [M+H]⁺.

Step 3) 3-cyclopropyl-N-(diphenylmethylene)imidazo[1,2-a]pyridin-7-amine

To a solution of 7-bromo-3-cyclopropylimidazo[1,2-a]pyridine (2.52 g,10.60 mmol) and diphenylmethanimine (2.64 g, 14.60 mmol) in toluene (40mL) were added Pd₂(dba)₃ (461.8 mg, 0.50 mmol), BINAP (626.9 mg, 0.96mmol) and t-BuONa (1.92 g, 20.00 mmol). The reaction mixture was stirredat 100° C. overnight, then cooled down to rt and quenched with water (50mL). The resulting mixture was extracted with EtOAc (100 mL×3), and thecombined organic phases were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/4) togive the title compound as black oil (1.04 g, yield 29.0%).

MS (ESI, pos. ion) m/z: 338.4 [M+H]⁺.

Step 4) 3-cyclopropylimidazo[1,2-a]pyridin-7-amine

To a solution of3-cyclopropyl-N-(diphenylmethylene)imidazo[1,2-a]pyridin-7-amine (1.02g, 3.02 mmol) in 1,4-dioxane (30 mL) was added a solution of HCl inEtOAc (30 mL, 120 mmol, 4 M) dropwise. The reaction mixture was stirredat rt overnight and then adjusted to pH=10 with a saturated Na₂CO₃aqueous solution. The resulting mixture was extracted with DCM (250mL×6). The combined organic phases were concentrated in vacuo. Theresidue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/10) to give the title compound as pale brown oil (333.7 mg,yield 63.7%).

MS (ESI, pos. ion) m/z: 174.3 [M+H]⁺.

Step 5) tert-butyl4-((5-chloro-2-((3-cyclopropylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate

To a suspension of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)piperidine-1-carboxylate (359.3 mg,1.04 mmol) and 3-cyclopropylimidazo[1,2-a]pyridin-7-amine (148.7 mg,0.86 mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)₂ (38.7 mg, 0.17mmol), BINAP (109.4 mg, 0.17 mmol) and Cs₂CO₃ (575.1 mg, 1.76 mmol). Thereaction mixture was stirred at 100° C. overnight and concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/20) to give the title compound as yellow oil (389.5mg, yield 93.7%).

MS (ESI, pos. ion) m/z: 484.4 [M+H]⁺.

Step 6)5-chloro-N²-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-((3-cyclopropylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate(383.9 mg, 0.79 mmol) in DCM (10 mL) was added a solution of HCl inEtOAc (10 mL, 40 mmol, 4 M). The reaction mixture was stirred at rt for0.5 hour and concentrated in vacuo. The residue was dissolved in water(30 mL) and the resulting mixture was adjusted to pH=10 with a saturatedNa₂CO₃ aqueous solution, then extracted with DCM (250 mL×3). Thecombined organic phases were washed with brine (250 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as yellow oil (278.3 mg, yield 91.4%).

MS (ESI, pos. ion) m/z: 384.4 [M+H]⁺.

Step 7)6-(4-((5-chloro-2-((3-cyclopropylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of5-chloro-N²-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine(350.9 mg, 0.91 mmol) and 6-chloropyridazine-3-carbonitrile (130.6 mg,0.92 mmol) in EtOH (20 mL) was added Et₃N (186.3 mg, 1.84 mmol). Thereaction mixture was stirred at rt overnight and quenched with water (30mL), then the resulting mixture was extracted with EtOAc (100 mL×3). Thecombined organic phases were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) togive the title compound as a beige solid (85.3 mg, yield 19.2%).

MS (ESI, pos. ion) m/z: 487.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.58 (s, 1H), 8.18 (d, J=7.3 Hz, 1H),7.97 (s, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.41 (s, 1H), 7.05 (s, 1H), 6.90(d, J=9.6 Hz, 1H), 5.32 (d, J=6.8 Hz, 1H), 4.64 (s, 1H), 4.50 (d, J=13.8Hz, 2H), 3.79-3.76 (m, 1H), 3.65-3.62 (m, 1H), 2.40 (d, J=14.0 Hz, 2H),2.03-1.99 (m, 3H), 1.85-1.80 (m, 2H), 0.85-0.82 (m, 2H), 0.77-0.72 (m,2H).

Example 156-(4-((5-chloro-2-((3-cyclopropylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)pyridazine-3-carbonitrile

Step 1) tert-butyl4-((5-chloro-2-((3-cyclopropylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-vl)amino)-3-ethylpiperidine-1-carboxylate

To a suspension of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(388.4 mg, 1.04 mmol) and 3-cyclopropylimidazo[1,2-a]pyridin-7-amine(149.4 mg, 0.86 mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)₂ (42.5mg, 0.19 mmol), BINAP (110.1 mg, 0.17 mmol) and Cs₂CO₃ (564.5 mg, 1.73mmol). The reaction mixture was stirred at 100° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound asyellow oil (402.2 mg, 91.1%).

MS (ESI, pos. ion) m/z: 512.3 [M+H]⁺.

Step 2)5-chloro-N²-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-N⁴-(3-ethylpiperidin-4-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-((3-cyclopropylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(392.3 mg, 0.77 mmol) in DCM (10 mL) was added a solution of HCl inEtOAc (10 mL, 40 mmol, 4M). The reaction mixture was stirred at rt for0.5 hour and concentrated in vacuo. The residue was dissolved in water(30 mL) and the resulting mixture was adjusted to pH=10 with a saturatedNa₂CO₃ aqueous solution, then extracted with DCM (250 mL×3). Thecombined organic phases were washed with brine (250 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as yellow oil (305.8 mg, yield 96.9%).

MS (ESI, pos. ion) m/z: 412.4 [M+H]⁺.

Step 3)6-(4-((5-chloro-2-((3-cyclopropylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of5-chloro-N²-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-N⁴-(3-ethylpiperidin-4-yl)pyrimidine-2,4-diamine(263.3 mg, 0.64 mmol) and 6-chloropyridazine-3-carbonitrile (92.8 mg,0.66 mmol) in EtOH (20 mL) was added Et₃N (157.8 mg, 1.56 mmol). Thereaction mixture was stirred at rt overnight and quenched with water (30mL), then the resulting mixture was extracted with EtOAc (100 mL×3). Thecombined organic phases were washed with brine (100 mL), dried overanhydrous Na₂SO₄, concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as a beige solid (96.6 mg, yield 29.3%).

MS (ESI, pos. ion) m/z: 515.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.47 (s, 1H), 8.17 (d, J=6.9 Hz, 1H),8.11-8.08 (m, 1H), 7.95 (s, 1H), 7.42 (d, J=9.5 Hz, 1H), 7.12 (s, 1H),6.89 (d, J=9.5 Hz, 1H), 5.22 (d, J=7.7 Hz, 1H), 4.68 (d, J=10.6 Hz, 1H),4.49 (d, J=9.6 Hz, 1H), 4.42-4.37 (m, 1H), 3.71-3.57 (m, 1H), 3.44-3.39(m, 1H), 2.02-1.99 (m, 2H), 1.68-1.62 (m, 4H), 1.10 (d, J=6.1 Hz, 3H),1.01 (t, J=7.0 Hz, 4H), 0.76-0.71 (m, 2H).

Example 166-(4-((5-chloro-2-((2,3-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)piperidine-1-carboxylate

To a solution of 2,4,5-trichloropyrimidine (2 g, 10.904 mmol) in ethanol(50 mL) were added tert-butyl 4-aminopiperidine-1-carboxylate (2.62 g,13.1 mmol) and TEA (2.21 g, 21.8 mmol). The reaction mixture was stirredat room temperature overnight and then concentrated in vacuo. Theresidue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/20 to 1/10) to give the title compound as a white solid (3.2 g,yield 85%).

MS (ESI, pos. ion) m/z: 347.3 [M+H]⁺.

Step 2) 7-bromo-2,3-dimethylimidazo[1,2-a]pyridine

To a solution of 4-bromopyridin-2-amine (2.02 g, 11.7 mmol) in ethanol(20 mL) was added 3-bromobutan-2-one (2.62 g, 17.4 mmol). The reactionwas stirred at 80° C. overnight and concentrated in vacuo. The residuewas dissolved in EtOAc (20 mL) and adjusted to pH=10 with a saturatedNaHCO₃ aqueous solution, then washed with brine (50 mL×3), the separatedorganic layer was dired over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by silica gel column chromatography(EtOAc/PE (v/v)=1/7) to to give the title compound as a yellow solid(1.6 g, yield 61%).

MS (ESI, pos. ion) m/z: 225.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67 (d, J=1.3 Hz, 1H), 7.65 (d, J=7.2Hz, 1H), 6.90-6.86 (m, 1H), 2.41 (s, 3H), 2.37 (s, 3H).

Step 3) N-(diphenylmethylene)-2,3-dimethylimidazo[1,2-a]pyridin-7-amine

To a solution of 7-bromo-2,3-dimethylimidazo[1,2-a]pyridine (1.6 g, 7.10mmol) and diphenylmethanimine (2.67 g, 14.7 mmol) in 1,4-dioxane (20 mL)were added BINAP (890 mg, 1.43 mmol), Pd₂(dba)₃ (653 mg, 0.713 mmol) andt-BuONa (1.41 g, 14.7 mmol). The reaction mixture was stirred at 85° C.overnight and concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc/PE (v/v)=1/1) to give the titlecompound as a brown solid (1.8 g, yield 78%).

MS (ESI, pos. ion) m/z: 326.4 [M+H]⁺.

Step 4) 3-methylimidazo[1,2-a]pyridin-7-amine

To a solution ofN-(diphenylmethylene)-2,3-dimethylimidazo[1,2-a]pyridin-7-amine (1.8 g,5.50 mmol) in DCM (10 mL) was added a solution of hydrogen chloride inEtOAc (20 mL, 60 mmol, 3 M). The reaction mixture was stirred at rtovernight and concentrated in vacuo. The residue was dissolved in EtOAc(20 mL) and the resulting mixture was adjusted to pH=10 with a saturatedNaHCO₃ aqueous solution, then extracted with EtOAc (50 mL×3). Thecombined organic phases were washed with brine (50 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography ((a solution of NH₃ in MeOH(7M))/DCM(v/v)=1/20) to give the title compound as a brown solid (300mg, yield 34%).

MS (ESI, pos. ion) m/z: 162.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.53 (d, J=7.2 Hz, 1H), 6.61 (d, J=1.5Hz, 1H), 6.30-6.26 (m, 1H), 2.31 (s, 3H), 2.29 (s, 3H).

Step 5) tert-butyl4-((5-chloro-2-((2,3-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate

To a solution of 3-methylimidazo[1,2-a]pyridin-7-amine (112 mg, 0.691mmol) and tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)piperidine-1-carboxylate (200 mg,0.576 mmol) in 1,4-dioxane (20 mL) were added BINAP (72 mg, 0.115 mmol),Pd(OAc)₂ (25 mg, 0.115 mmol) and Cs₂CO₃ (376 mg, 1.15 mmol). The mixturewas stirred at 100° C. overnight and concentrated in vacuo. The residuewas purified by silica gel column chromatography ((a solution of NH₃ inMeOH (7M))/DCM (v/v)=1/30) to give the title compound as a yellow solid(150 mg, yield 55.2%).

MS (ESI, pos. ion) m/z: 472.5 [M+H]⁺.

Step 6)5-chloro-N²-(2,3-dimethylimidazo[1,2-a]pyridin-7-yl)-N⁴-(piperidin-4-yppyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-((2,3-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate(150 mg, 0.317 mmol) in DCM (20 mL) was added a solution of hydrogenchloride in EtOAc (20 mL, 60 mmol, 3 M). The reaction mixture wasstirred at rt overnight and concentrated in vacuo. The residue wasdissolved in EtOAc (20 mL) and the resulting mixture was adjusted topH=10 with a saturated NaHCO₃ aqueous solution, then extracted withEtOAc (50 mL×3). The combined organic phases were washed with brine (50mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by preparative TLC (MeOH/DCM(v/v)=1/10) toafford the title compound as a yellow solid (90 mg, yield 76.2%).

MS (ESI, pos. ion) m/z: 372.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.04 (s, 1H), 7.90 (s, 1H), 7.71 (s,1H), 6.96 (s, 1H), 4.28 (s, 1H), 3.34-3.29 (m, 2H), 3.19-3.14 (m, 2H),2.37 (s, 6H), 2.22-2.17 (m, 2H), 1.91-1.86 (m, 2H).

Step 7)6-(4-((5-chloro-2-((2,3-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of5-chloro-N²-(2,3-dimethylimidazo[1,2-a]pyridin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine(87 mg, 0.234 mmol) and 6-chloronicotinonitrile (53 mg, 0.379 mmol) inethanol (10 mL) was added TEA (85 mg, 0.840 mmol). The mixture wasstirred at rt overnight and concentrated in vacuo. The residue waspurified by silica gel column chromatography ((a solution of NH₃ in MeOH(7M))/DCM (v/v)=1/20) to give the title compound as a yellow solid (60mg, yield 54%).

MS (ESI, pos. ion) m/z: 475.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.01 (d, J=1.5 Hz, 1H), 7.95 (s, 1H),7.67 (d, J=7.3 Hz, 1H), 7.44 (d, J=9.6 Hz, 1H), 7.04 (s, 1H), 6.90 (d,J=9.6 Hz, 1H), 6.84 (dd, J=7.3, 2.0 Hz, 1H), 5.21 (d, J=7.0 Hz, 1H),4.55-4.50 (m, 2H), 4.44-4.40 (m, 1H), 3.51-3.46 (m, 2H), 2.36 (s, 6H),2.37-2.31 (m, 2H), 1.60-1.57 (m, 2H).

Example 176-(4-((5-chloro-2-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

Step 1)6-(4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

To a solution of 2,5-dichloro-N-(3-ethylpiperidin-4-yl)pyrimidin-4-amine(806.2 mg, 2.93 mmol) in ethanol (20 mL) were added TEA (0.6 mL, 4 mmol)and 6-chloropyridine-3-carbonitrile (487.4 mg, 3.52 mmol), the reactionmixture was heated to refluxed and stirred for 3 hours. The mixture wasconcentrated in vacuo, and the residue was purified by silical gelcolumn chromatography (EtOAc/PE (v/v)=1/5 to 1/3 to give the titleproduct as a white solid (182.0 mg, yield 17%).

MS (ESI, pos. ion) m/z: 377.2 [M+H]⁺.

Step 2)N-(diphenylmethylene)-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-amine

To a solution of 7-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine (945mg, 4.46 mmol) and diphenylmethanimine (1.22 g, 6.72 mmol) in1,4-dioxane (20 mL) were added BINAP (558 mg, 0.896 mmol), Pd₂(dba)₃(410 mg, 0.448 mmol) and t-BuONa (861 mg, 8.96 mmol). The reaction wasstirred at 85° C. for 4 hours and concentrated in vacuo. The residue wasused for next step directly without further purification.

MS (ESI, pos. ion) m/z: 313.4 [M+H]⁺.

Step 3) 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-amine

To a solution ofN-(diphenylmethylene)-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-amine(1.4 g, 4.48 mmol) in DCM (10 mL) was added a solution of hydrogenchloride in EtOAc (20 mL, 60 mmol, 3 M). The reaction mixture wasstirred at rt overnight and concentrated in vacuo. The residue wasdissolved in EtOAc (20 mL) and the resulting mixture was adjusted topH=10 with a saturated NaHCO3 aqueous solution, then extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine (50mL×3), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography ((a solution ofNH₃ in MeOH (7M))/DCM(v/v)=1/20) to give the title compound as a brownsolid (176 mg, yield 27%).

MS (ESI, pos. ion) m/z: 149.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.57 (d, J=7.4 Hz, 1H), 6.48 (d, J=1.4Hz, 1H), 6.39-6.35 (m, 1H), 2.54 (s, 3H).

Step 4)6-(4-((5-chloro-2-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile(80 mg, 0.212 mmol) and 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-amine(40 mg, 0.270 mmol) in 1,4-dioxane (20 mL) were added BINAP (26 mg,0.041 mmol), Pd(OAc)₂ (9 mg, 0.040 mmol) and Cs₂CO₃ (138 mg, 0.424mmol). The mixture was stirred at 100° C. overnight and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography ((a solution of NH₃ in MeOH (7M))/DCM (v/v)=1/20) to givethe title compound as a yellow solid (45 mg, 43.4%).

MS (ESI, pos. ion) m/z: 489.5 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.41 (d, J=2.1 Hz, 1H), 8.36 (s, 1H),7.98 (s, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.61 (dd, J=9.0, 2.3 Hz, 1H), 7.36(s, 1H), 6.89 (d, J=6.5 Hz, 1H), 6.65 (d, J=9.1 Hz, 1H), 5.18 (d, J=8.4Hz, 1H), 4.62 (d, J=13.0 Hz, 1H), 4.41 (d, J=13.4 Hz, 1H), 4.27-4.16 (m,1H), 3.39-3.28 (m, 1H), 2.95 (dd, J=13.5, 10.9 Hz, 1H), 2.70 (s, 3H),2.34-2.28 (m, 1H), 1.59-1.44 (m, 2H), 1.39-1.28 (m, 2H), 1.01 (t, J=7.5Hz, 3H).

Example 186-(4-((5-chloro-2-(imidazo[1,2-b]pyridazin-7-ylamino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 3,4,5-trichloropyridazine

A mixture of 4,5-dichloropyridazin-3-one (20.06 g, 122.3 mmol) and POCl₃(117 mL, 1280 mmol) was stirred at reflux for 3 h. The reaction mixturewas cooled down to rt, and poured into a mixture of water and ice (100mL), and the resulting mixture was adjusted to pH=10 with a saturatedNa₂CO₃ aqueous solution, then extracted with EtOAc (250 mL×3). Thecombined organic phases were washed with brine (250 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/30) togive the title compound as a white solid (17.80 g, yield 79.3%).

¹H NMR (400 MHz, CDCl₃): δ (ppm) 9.12 (s, 1H).

Step 2) 5,6-dichloropyridazin-4-amine

A mixture of 3,4,5-trichloropyridazine (17.79 g, 96.99 mmol) and asolution of NH₃ in THF (250 mL, 750 mmol, 3 M) was stirred at 125° C. ina sealed tube for 5 h. The reaction mixture was concentrated in vacuoand the residue was purified by silica gel column chromatography(EtOAc/PE (v/v)=1/2) to give the title compound as a white solid (4.01g, yield 25%).

MS (ESI, pos. ion) m/z: 164.1 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.60 (s, 1H), 4.89 (s, 2H).

Step 3) 5-chloro-6-hydrazinylpyridazin-4-amine

A mixture of 5,6-dichloropyridazin-4-amine (4.01 g, 24.5 mmol) andhydrazine hydrate (80% [w/w] in water, 26.20 g, 419 mmol) was stirred at90° C. for 3 hours. The reaction mixture was cooled down to rt and water(20 mL) was added to the mixture, then a yellow solid was precipitateout. Filtered, and collected the filter cake to give the title compoundas a yellow solid (3.51 g, yield 90%).

MS (ESI, pos. ion) m/z: 160.1 [M+H]⁺.

Step 4) 4-chloropyridazine-3,5-diamine

To a suspension of 5-chloro-6-hydrazinopyridazin-4-amine (3.51 g, 22.0mmol) in ethanol (50 mL) was added Raney Ni (7.26 g). The reactionmixture was placed in a high pressure autoclave and stirred at 55° C.under 3 MPa H₂ atmosphere for 3 h. The resulting mixture was filteredthrough a pad of Celite. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as a brown solid (1.80 g, yield57%).

MS (ESI, pos. ion) m/z: 145.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 7.98 (s, 1H), 6.28 (s, 2H), 6.04 (s,2H).

Step 5) pyridazine-3,5-diamine

To a suspension of 4-chloropyridazine-3,5-diamine (6.00 g, 41.50 mmol)in EtOH (150 mL) were added NaOH (1.67 g, 41.75 mmol) and Pd/C (mass%=10%, 660.0 mg). The suspension was stirred at rt under a H₂ atmosphereovernight and then filtered through a pad of Celite. The filtrate wasconcentrated in vacuo to give the title compound as a red brown solid(4.50 g, yield 98%).

MS (ESI, pos. ion) m/z: 111.2 [M+H]⁺.

Step 6) imidazo[1,2-b]pyridazin-7-amine

A mixture of pyridazine-3,5-diamine (1.53 g, 13.9 mmol) and2-chloroacetaldehyde (40% [w/w] in water, 4.32 g, 22.0 mmol) in water(50 mL) was stirred at 100° C. overnight, then cooled down to rt, andadjusted to pH=10 with a saturated Na₂CO₃ aqueous solution. Theresulting mixture was extracted with DCM (250 mL×3). The combinedorganic phases were washed with brine (250 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as brown oil (668.9 mg, yield 35.9%).

MS (ESI, pos. ion) m/z: 135.2 [M+H]⁺.

Step 7)6-(4-((5-chloro-2-(imidazo[1,2-b]pyridazin-7-ylamino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(176.4 mg, 0.50 mmol) and imidazo[1,2-b]pyridazin-7-amine (83.6 mg, 0.62mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)₂ (23.6 mg, 0.10 mmol),BINAP (63.7 mg, 0.10 mmol) and Cs₂CO₃ (332.5 mg, 1.00 mmol). Thereaction mixture was stirred at 100° C. for 7.5 hours and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/50) to give the title compound as abeige solid (65.0 mg, yield 28.8%).

MS (ESI, pos. ion) m/z: 447.4 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃ and CD₃OD) δ (ppm): 8.62 (s, 1H), 8.44-8.35 (m,2H), 8.35 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.64 (dd, J=9.0, 2.3 Hz,1H), 7.57 (s, 1H), 6.72 (d, J=9.0 Hz, 1H), 4.44 (d, J=13.0 Hz, 2H),4.37-4.32 (m, 1H), 3.36-3.29 (m, 2H), 2.25 (d, J=12.1 Hz, 2H), 1.63-1.56(m, 2H).

Example 196-(4-((5-chloro-2-(imidazo[1,2-b]pyridazin-7-ylamino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) tert-butyl4-((5-chloro-2-(imidazo[1,2-b]pyridazin-7-ylamino)pyrimidin-4-yl)amino)piperidine-1-carboxylate

To a suspension of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)piperidine-1-carboxylate (743.7 mg,2.14 mmol) and imidazo[1,2-b]pyridazin-7-amine (314.8 mg, 2.35 mmol) in1,4-dioxane (50 mL) were added Pd(OAc)₂ (112.3 mg, 0.50 mmol), BINAP(311.4 mg, 0.49 mmol) and Cs₂CO₃ (1.37 g, 4.12 mmol). The reactionmixture was stirred at 100° C. for 7 hours and then concentrated invacuo. The residue was purified by silica gel column chromatography(EtOAc/PE (v/v)=1/1) to give the title compound as a yellow solid (157.1mg, yield 16.5%).

MS (ESI, pos. ion) m/z: 445.4 [M+H]⁺.

Step 2)5-chloro-N²-(imidazo[1,2-b]pyridazin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-(imidazo[1,2-b]pyridazin-7-ylamino)pyrimidin-4-yl)amino)piperidine-1-carboxylate(143.2 mg, 0.32 mmol) in DCM (10 mL) was added a solution of HCl inEtOAc (10 mL, 40 mmol, 4 M). The reaction mixture was stirred at rt for0.5 hour and then concentrated in vacuo. The residue was dissolved inwater (10 mL) and the resulting mixture was adjusted to pH=10 with asaturated Na₂CO₃ aqueous solution, then extracted with DCM (100 mL×3).The combined organic phases were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as yellow oil (111.0 mg, yield 100%).

MS (ESI, pos. ion) m/z: 345.0 [M+H]⁺.

Step 3)6-(4-((5-chloro-2-(imidazo[1,2-b]pyridazin-7-ylamino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of5-chloro-N²-(imidazo[1,2-b]pyridazin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine(95.7 mg, 0.28 mmol) and 6-chloropyridazine-3-carbonitrile (96.3 mg,0.69 mmol) in EtOH (20 mL) was added Et₃N (192.0 mg, 1.90 mmol). Thereaction mixture was stirred at rt overnight and then quenched withwater (30 mL). The resulting mixture was extracted with EtOAc (100mL×3). The combined organic phases were washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/40) to give the title compound as a beige solid (45.8 mg, yield36.8%).

MS (ESI, pos. ion) m/z: 448.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃ and MeOH-d4) δ (ppm): 8.51 (d, J=1.3 Hz, 1H),8.36 (s, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 7.41 (d, J=9.7Hz, 1H), 6.93 (d, J=9.7 Hz, 1H), 4.46 (d, J=13.8 Hz, 2H), 4.38-4.26 (m,1H), 2.22 (dd, J=12.3, 1.4 Hz, 3H), 1.97-1.86 (m, 1H), 1.60-1.51 (m,3H).

Example 206-(4-((5-chloro-2-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(70 mg, 0.199 mmol) and 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-amine(37 mg, 0.249 mmol) in 1,4-dioxane (20 mL) were added BINAP (25 mg,0.040 mmol), Pd(OAc)₂ (8 mg, 0.039 mmol) and Cs₂CO₃ (130 mg, 0.398mmol). The mixture was stirred at 105° C. overnight and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography ((MeOH/DCM (v/v)=1/20) to give the title compound as ayellow solid (30 mg, yield 32.5%).

MS (ESI, pos. ion) m/z: 462.4 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.86 (s, 1H), 8.34 (s, 1H), 8.25 (d,J=7.4 Hz, 1H), 8.10 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.45 (d, J=9.7 Hz,1H), 4.68-4.64 (m, 2H), 4.59-4.55 (s, 1H), 4.42-4.38 (m, 1H), 2.61 (s,3H), 2.10-2.05 (m, 2H), 2.02-1.98 (m, 1H), 1.72-1.67 (m, 2H).

Example 216-(4-((5-chloro-2-((3-methylimidazo[1,2-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 3-methylimidazo[1,2-b]pyridazin-7-amine

To pyridazine-3,5-diamine (0.80 g, 7.30 mmol) was added a solution of2-chloropropanal in chloroform and n-hexane (70.0 mL, 39.9 mmol, 0.57M). The mixture was heated at 80° C. overnight and then concentrated invacuo. The residue was diluted with saturated Na₂CO₃ aqueous solution(20 mL), and the resulting mixture was extracted with DCM (50 mL×3) anda mixed solvent of DCM/MeOH (10/1 (v/v), 50 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=100/1 to 50/1 to 20/1) toafford the title compound as a yellow solid (0.37 g, yield 34%).

MS (ESI, pos. ion) m/z: 149.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.97 (d, J=2.6 Hz, 1H), 7.27 (s, 1H),6.97 (d, J=2.6 Hz, 1H), 3.95 (s, 2H), 2.48 (s, 3H).

Step 2)6-(4-((5-chloro-2-((3-methylimidazo[1,2-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(0.15 g, 0.43 mmol) in anhydrous 1,4-dioxane (10.0 mL) were added3-methylimidazo[1,2-b]pyridazin-7-amine (0.098 g, 0.66 mmol), Pd(OAc)₂(0.021 g, 0.095 mmol), BINAP (0.056 g, 0.089 mmol) and Cs₂CO₃ (0.28 g,0.87 mmol). The mixture was degassed and refilled with N₂ for severaltimes and heated to 100° C. and stirred for 5 h. The mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=100/1 to 50/1to 30/1) to afford the crude product (0.14 g, yield 70%). The crudeproduct was purified by preparative TLC (DCM/(a solution of NH₃ in MeOH(3M)) (v/v)=40/1) to afford the title compound as a yellow solid (32 mg,yield 16%).

MS (ESI, pos. ion) m/z: 461.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.51-8.35 (m, 3H), 7.98 (s, 1H), 7.61(dd, J=9.0, 2.3 Hz, 1H), 7.43 (s, 1H), 7.16 (s, 1H), 6.65 (d, J=9.0 Hz,1H), 5.25 (d, J=7.3 Hz, 1H), 4.49-4.39 (m, 2H), 4.39-4.28 (m, 1H),3.38-3.25 (m, 2H), 2.53 (s, 3H), 2.31-2.20 (m, 2H), 1.60-1.54 (m, 2H).

Example 226-(4-((5-chloro-2-((3,6-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 4-bromo-3-methylpyridine 1-oxide

To a solution of 4-bromo-3-methylpyridine hydrochloride (10 g, 47.966mmol) in DCM (200 mL) was added mCPBA (11.69 g, 57.58 mmol) at 0° C. Thereaction mixture was allowed to moved to rt and stirred overnight andthen concentrated in vacuo. The residue was dissolved in water (250 mL)and the resulting mixture was adjusted to pH=8-9 with a saturated Na₂CO₃aqueous solution, then extracted with DCM (250 mL×3). The combinedorganic layers were washed with brine (250 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the titlecompound as a yellow solid (4.68 g, yield 51.9%).

MS (ESI, pos. ion) m/z: 188.2 [M+H]⁺.

Step 2) 4-bromo-N-(tert-butyl)-5-methylpyridin-2-amine

To a solution of 4-bromo-3-methylpyridine 1-oxide (4.68 g, 24.9 mmol)and 2-methylpropan-2-amine (9.10 g, 124 mmol) in DCM (200 mL) was added4-methylbenzenesulfonic anhydride (16.2 g, 49.6 mmol) at 0° C. Themixture was stirred at 0° C. for 1 hour and allowed to moved to rt andstirred overnight. The residue was dissolved in water (250 mL) and theresulting mixture was extracted with DCM (250 mL×3). The combinedorganic layers were washed with brine (250 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (PE/EtOAc (v/v)=100/1 to 50/1) to give thetitle compound as a yellow solid (1.35 g, yield 22.3%).

MS (ESI, pos. ion) m/z: 243.2 [M+H]⁺.

Step 3) 4-bromo-5-methylpyridin-2-amine

To a solution of 4-bromo-N-(tert-butyl)-3-methylpyridin-2-amine (2.35 g,9.67 mmol) in toluene (12 mL) was added 2,2,2-trifluoroacetic acid (12mL). The reaction mixture was stirred at 70° C. for overnight andconcentrated in vacuo. The residue was dissolved in water (20 mL) andthe resulting mixture was adjusted to pH=8-9 with a saturated NaHCO₃aqueous solution, then mixture was concentrated in vacuo. The residuewas purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50)to give the title compound as a yellow solid (1.43 g, yield 79.1%).

MS (ESI, pos. ion) m/z: 187.2 [M+H]⁺.

Step 4) 7-bromo-3,6-dimethylimidazo[1,2-a]pyridine

To a solution of 4-bromo-5-methylpyridin-2-amine (1.5 g, 8.0 mmol) and2-chloropropanal (140 mL, 80 mmol) in ethanol (100 mL) was added4-methylbenzenesulfonic acid (280 mg, 1.626 mmol). The mixture wasstirred at 100° C. overnight and then concentrated in vacuo. The residuewas purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1to 50/1) to give the title compound as a yellow solid (820 mg, yield45%).

MS (ESI, pos. ion) m/z: 225.2 [M+H]⁺.

Step 5) N-(diphenylmethylene)-3,6-dimethylimidazo[1,2-a]pyridin-7-amine

To a solution of 7-bromo-3,6-dimethylimidazo[1,2-a]pyridine (820 mg,3.6431 mmol), diphenylmethanimine (991 mg, 5.469 mmol) and t-BuONa(700.5 mg, 7.289 mmol) in 1,4-dioxane (50 mL) were added BINAP (227 mg,0.3645 mmol) and Pd₂(dba)₃ (172 mg, 0.1822 mmol). The mixture wasdegassed for 5 min and refilled with N2 and stirred at 105° C. for 4 h,then concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/1) to give the title compound asa yellow solid (667 mg, yield 56.26%).

MS (ESI, pos. ion) m/z: 326.4 [M+H]⁺.

Step 6) 3,6-dimethylimidazo[1,2-a]pyridin-7-amine

To a solution ofN-(diphenylmethylene)-3,6-dimethylimidazo[1,2-a]pyridin-7-amine (667 mg,2.050 mmol) in DCM (20 mL) was added a solution of hydrogen chloride inEtOAc (11 mL, 33 mmol, 3M). The reaction mixture was stirred at rt for 4hours and concentrated in vacuo. The residue was dissolved in water (15mL) and the resulting mixture was adjusted to pH=10 with a saturatedNaHCO₃ aqueous solution, then the mixture was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=20/1 to 10/1) to give the title compound as a yellow solid (270mg, yield 81.71%).

MS (ESI, pos. ion) m/z: 162.2 [M+H]⁺.

Step 7)6-(4-((5-chloro-2-((3,6-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(0.15 g, 0.43 mmol) in n-BuOH (5.0 mL) were added3,6-dimethylimidazo[1,2-a]pyridin-7-amine (0.086 g, 0.53 mmol) and DIPEA(0.14 g, 1.05 mmol). The mixture was placed in a sealed vial thendegassed and refilled with N₂ for several times and then, stirred at150° C. for 48 hours and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to50/1 to DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=50/1 to 20/1 to 10/1to 2/1) to afford the crude product. The crude product was purifiedtwice by preparative TLC (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=40/1) to afford the title compound as a light yellow solid (62 mg,yield 30%).

MS (ESI, pos. ion) m/z: 475.2 [M+H]⁺;

¹H NMR (400 MHz, MeOH-d₄) δ (ppm): 8.26 (s, 1H), 8.24 (s, 1H), 8.16 (s,1H), 8.15-8.13 (m, 1H), 7.69 (d, J=9.7 Hz, 1H), 7.33 (d, J=9.7 Hz, 1H),4.71-4.54 (m, 3H), 3.44-3.34 (m, 2H), 2.54 (s, 3H), 2.32 (s, 3H),2.23-2.14 (m, 2H), 1.84-1.71 (m, 2H).

Example 236-(4-((5-chloro-2-((3-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(0.15 g, 0.43 mmol) in anhydrous 1,4-dioxane (10.0 mL) were added3-methylimidazo[1,2-a]pyridin-7-amine (0.10 g, 0.67 mmol), Pd(OAc)₂(0.020 g, 0.090 mmol), BINAP (0.055 g, 0.088 mmol) and Cs₂CO₃ (0.30 g,0.93 mmol). Under the N₂ atmosphere, the mixture was heated to 100° C.and stirred overnight and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/(a solution of NH₃ inMeOH (3M)) (v/v)=100/1 to 50/1) to afford the title compound as a lightyellow solid (95 mg, yield 48%).

MS (ESI, pos. ion) m/z: 460.5 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.41 (d, J=2.2 Hz, 1H), 8.14 (d, J=1.6Hz, 1H), 7.96 (s, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.60 (dd, J=9.0, 2.3 Hz,1H), 7.28 (s, 1H), 7.11 (s, 1H), 6.85 (dd, J=7.4, 1.9 Hz, 1H), 6.65 (d,J=9.1 Hz, 1H), 5.21 (d, J=7.2 Hz, 1H), 4.47-4.32 (m, 3H), 3.42-3.29 (m,2H), 2.44 (s, 3H), 2.32-2.23 (m, 2H), 1.62-1.51 (m, 2H).

Example 246-(4-((5-chloro-2-((6-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 7-bromo-6-methylimidazo[1,2-a]pyridine

To a 25 mL sealed tube was added 4-bromo-5-methylpyridin-2-amine (880mg, 4.7049 mmol) and a solution of 2-chloroacetaldehyde in water (8 mL,mass %=40%). The reaction mixture was heated to 100° C. and stirred for20 hours. The resulting mixture was adjusted to pH=10 with a saturatedNa₂CO₃ aqueous solution and extracted with a mixed solvent of DCM/MeOH(10/1 (v/v), 100 mL×3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=100/1) to give thetitle compound as a yellow solid (780 mg, yield 78.5%).

MS (ESI, pos.ion) m/z: 211.2 [M+H]⁺.

Step 2) N-(diphenylmethylene)-6-methylimidazo[1,2-a]pyridin-7-amine

A mixture of 7-bromo-6-methylimidazo[1,2-a]pyridine (780 mg, 3.6956mmol), diphenylmethanimine (816.4 mg, 4.506 mmol), t-BuONa (713.6 mg,7.426 mmol), BINAP (232.5 mg, 0.3734 mmol), Pd₂(dba)₃ (334.8 mg, 0.3656mmol) in 1,4-dioxane (20 mL) was heated to 100° C. and stirred overnightunder N₂ atmosphere. The reaction solution was diluted with water (50mL), the resulting mixture was extracted with a mixed solvent ofDCM/MeOH (10/1 (v/v), 100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica gel column chromatography (DCM/MeOH (v/v)=80/1)to give the title compound as a yellow solid (710 mg, yield 61.7%).

MS (ESI, pos.ion) m/z: 312.1 [M+H]⁺.

Step 3) 6-methylimidazo[1,2-a]pyridin-7-amine

N-(diphenylmethylene)-6-methylimidazo[1,2-a]pyridin-7-amine (710 mg,2.280 mmol) was dissolved in a solution of hydrogen chloride in EtOAc(20 mL, 20 mmol, 1 M). The reaction solution was stirred at rt overnightand then washed with water (40 mL×2). The combined aqueous phases wereadjusted to pH=12 with NaOH powder, the resulting mixture was extractedwith a mixed solvent of DCM/MeOH (10/1 (v/v), 100 mL×5). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (7M)) (v/v)=80/1) to givethe title compound as a yellow solid (320 mg, yield 95.36%).

MS (ESI, pos.ion) m/z: 148.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃+CD₃OD) δ (ppm): 7.77 (s, 1H), 7.30 (s, 1H), 6.69(s, 1H), 2.15 (s, 3H).

Step 4)6-(4-((5-chloro-2-((6-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a 25 mL sealed tube were added 6-methylimidazo[1,2-a]pyridin-7-amine(203.4 mg, 1.382 mmol),6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile (497.8 mg, 1.421 mmol), DIPEA (0.8 mL, 5 mmol)and n-BuOH (6 mL) and the reaction solution was heated to 150° C. andstirred for 2 days. The reaction mixture was concentrated in vacuo andthe residue was purified by silica gel column chromatography (DCM/(asolution of NH₃ in MeOH (7M)) (v/v)=80/1) to give the title compound asa white solid (11.4 mg, yield 1.79%).

MS (ESI, pos.ion) m/z: 461.4 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.45 (s, 1H), 8.39 (d, J=2.6 Hz, 1H),8.33 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.93 (s, 1H), 7.89 (d, J=9.7 Hz,1H), 7.44 (d, J=9.8 Hz, 1H), 4.63-4.51 (m, 3H), 2.19 (s, 3H), 2.05-1.91(m, 4H), 1.74-1.64 (m, 2H).

Example 256-(4-((5-chloro-2-((3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 6-hydrazinylpyridazin-4-amine

To a solution of 5-chloro-6-hydrazinylpyridazin-4-amine (5.02 g, 31.3mmol) in methanol (60 mL) were added Pd/C (mass %=10%, 503 mg) and NaOH(1.25 g, 31.3 mmol). The mixture was placed in a high pressure autoclaveand stirred at rt under 2 MPa H2 atmosphere overnight and then filtered.The filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography (a solution of NH₃ in MeOH(7M))/DCM(v/v)=1/30) to give the title compound as a yellow solid (1.3g, yield 33%).

MS (ESI, pos. ion) m/z: 126.3 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.91 (d, J=2.3 Hz, 1H), 7.16 (s, 1H),6.02 (d, J=2.3 Hz, 1H), 5.97 (s, 2H).

Step 2) 3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-7-amine

To a solution of 6-hydrazinylpyridazin-4-amine (5.02 g, 31.3 mmol) inEtOH (30 mL) were added Et₃N (2.43 g, 24.0 mmol) and acetic anhydride(1.22 g, 12.2 mmol). The reaction mixture was stirred at 90° C.overnight and concentrated in vacuo. The residue was purified by silicagel column chromatography (a solution of NH₃ in MeOH(7M))/DCM(v/v)=1/30) to give the title compound as a yellow solid (400mg, yield 33.6%).

MS (ESI, pos. ion) m/z: 150.3 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 8.14 (d, J=2.2 Hz, 1H), 6.63 (s, 1H),6.26 (s, 2H), 2.46 (s, 3H).

Step 3)6-(4-((5-chloro-2-((3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(100 mg, 0.286 mmol) and3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-7-amine (65 mg, 0.436 mmol) in1,4-dioxane (20 mL) were added BINAP (35 mg, 0.056 mmol), Cs₂CO₃ (138mg, 0.424 mmol) and Pd(OAc)₂ (12 mg, 0.053 mmol). The mixture wasstirred at 105° C. overnight and then concentrated in vacuo. The residuewas purified by silica gel column chromatography ((MeOH/DCM (v/v)=1/30)to give the title compound as a yellow solid (65 mg, yield 49.1%).

MS (ESI, pos. ion) m/z: 462.5 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 462.1675 [M+H]⁺, calculated value forC₂₁H₂₀ClN₁₁ [M+H]⁺ is 462.1592;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.05 (s, 1H), 8.64-6.48 (m, 2H),8.49 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 7.85 (dd, J=9.1, 2.1 Hz, 1H), 7.20(d, J=7.7 Hz, 1H), 7.01 (d, J=9.1 Hz, 1H), 4.59-4.54 (m, 2H), 4.36-4.22(m, 1H), 3.13-3.05 (m, 2H), 2.60 (s, 3H), 2.03-1.98 (m, 2H), 1.69-1.59(m, 2H);

¹³C NMR (100 MHz, DMSO-d6) δ (ppm): 158.91, 157.32, 156.86, 153.25,152.61, 144.80, 144.42, 142.14, 140.00, 132.96, 118.77, 106.50, 105.57,102.33, 94.88, 48.67, 43.82, 30.46, 9.18.

Example 266-(4-((5-chloro-2-((6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 3-bromo-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine

To a solution of 4-bromopyridin-2-amine (1.94 g, 11.21 mmol) and2-chlorocyclohexanone (2.62 g, 19.76 mmol) in n-BuOH (25 mL) was added4-methylbenzenesulfonic acid hydrate (400.9 mg, 2.11 mmol). The reactionmixture was stirred at 150° C. overnight, then cooled down to rt andconcentrated in vacuo. The residue was diluted with water (30 mL), andthe resulting mixture was adjusted to pH=10 with a saturated Na₂CO₃aqueous solution, and then extracted with DCM (100 mL×3). The combinedorganic phases were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (EtOAc/PE (v/v)=1/8) to give the titlecompound as a yellow solid (2.33 g, yield 82.7%).

MS (ESI, pos. ion) m/z: 251.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.71 (d, J=9.0 Hz, 2H), 7.66 (d, J=7.1Hz, 1H), 6.87 (dd, J=7.1, 1.6 Hz, 1H), 2.83 (t, J=5.9 Hz, 2H), 2.75-2.68(m, 2H), 2.03-1.88 (m, 4H).

Step 2)N-(diphenylmethylene)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-amine

To a solution of3-bromo-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (2.28 g, 9.08mmol) and diphenylmethanimine (2.48 g, 13.69 mmol) in 1,4-dioxane (40mL) were added Pd₂(dba)₃ (424.5 mg, 0.46 mmol), BINAP (596.9 mg, 0.91mmol) and t-BuONa (1.75 g, 18.21 mmol). The reaction mixture was stirredat 100° C. overnight, then cooled down to rt and concentrated in vacuo.The residue was purified by silica gel column chromatography (EtOAc/PE(v/v)=2/1) to give the title compound as a yellow solid (1.29 g, yield40.4%).

MS (ESI, pos. ion) m/z: 352.4 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.75 (d, J=7.2 Hz, 2H), 7.54 (d, J=7.1Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.41 (t, J=7.4 Hz, 2H), 7.29-7.26 (m,3H), 7.19-7.16 (m, 2H), 6.84 (d, J=1.3 Hz, 1H), 6.29 (dd, J=7.1, 1.9 Hz,1H), 2.78 (t, J=5.8 Hz, 2H), 2.66 (t, J=5.8 Hz, 2H), 1.99-1.83 (m, 4H).

Step 3) 6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-amine

To a solution ofN-(diphenylmethylene)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-amine(1.25 g, 3.56 mmol) in 1,4-dioxane (35 mL) was added a solution of HClin EtOAc (35 mL, 140 mmol, 4M) dropwise. The reaction mixture wasstirred at rt overnight and adjusted to pH=10 with a Na₂CO₃ powder, thenextracted with DCM (250 mL×6). The combined organic phases wereconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/10) to give the title compound as abrown solid (666.0 mg, yield 100%).

MS (ESI, pos. ion) m/z: 188.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.49 (d, J=7.2 Hz, 1H), 6.58 (d, J=1.6Hz, 1H), 6.24 (dd, J=7.2, 2.0 Hz, 1H), 3.75 (s, 2H), 2.70 (t, J=5.8 Hz,2H), 2.60 (t, J=5.9 Hz, 2H), 1.94-1.75 (m, 4H).

Step 4)6-(4-((5-chloro-2-((6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(69.7 mg, 0.20 mmol) and6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-amine (73.1 mg, 0.39mmol) in 1,4-dioxane (8 mL) were added Pd(OAc)₂ (9.4 mg, 0.04 mmol),BINAP (98%, 28.0 mg, 0.04 mmol) and Cs₂CO₃ (98%, 137.8 mg, 0.41 mmol).The reaction mixture was stirred at 100° C. overnight and concentratedin vacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/30) to give the title compound as a beige solid (59.1mg, yield 59.3%).

MS (ESI, pos. ion) m/z: 501.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 501.2022 [M+H]⁺, calculated value forC₂₅H₂₆ClN₁₀ [M+H]⁺ is 501.2030;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.56 (s, 1H), 8.09 (s, 1H), 8.05 (d,J=7.5 Hz, 1H), 8.03 (s, 1H), 7.87 (d, J=9.7 Hz, 1H), 7.44 (d, J=9.7 Hz,1H), 7.14 (dd, J=7.3, 1.6 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 4.63 (d,J=12.4 Hz, 2H), 4.48-4.31 (m, 1H), 3.26 (t, J=12.5 Hz, 2H), 2.74-2.56(m, 4H), 2.06 (d, J=11.0 Hz, 2H), 1.92-1.76 (m, 4H), 1.74-1.64 (m, 2H);

¹³C NMR (100 MHz, DMSO-d6) δ (ppm): 159.1, 158.2, 153.8, 131.6, 123.7,111.6, 107.0, 100.4, 48.7, 44.3, 30.9, 24.9, 23.5, 22.8, 20.1.

Example 276-(4-((5-chloro-2-((2-methylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(0.15 g, 0.43 mmol) in anhydrous 1,4-dioxane (10 mL) were added2-methylimidazo[1,2-a]pyridin-7-amine (0.097 g, 0.66 mmol), Pd(OAc)₂(0.020 g, 0.087 mmol), BINAP (0.055 g, 0.089 mmol) and Cs₂CO₃ (0.30 g,0.92 mmol). The mixture was degassed and refilled with N₂ for severaltimes and then heated to 100° C. and stirred for 3 h. The mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=100/1 to 50/1to 30/1), to give the crude product. The crude product was stirred withEtOAc (3 mL), filtered and the filter cake was collected and dried invacuo to afford the title compound as a white solid (95 mg, yield 48%).

MS (ESI, pos. ion) m/z: 461.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 461.1716 [M+H]⁺, calculated value forC₂₂H₂₂ClN₁₀ [M+H]⁺ is 461.1712;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.51 (s, 1H), 8.26 (d, J=7.3 Hz, 1H),8.08-8.01 (m, 2H), 7.88 (d, J=9.7 Hz, 1H), 7.49-7.40 (m, 2H), 7.06 (dd,J=7.4, 1.9 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.70-4.58 (m, 2H), 4.45-4.32(m, 1H), 3.29-3.20 (m, 2H), 2.24 (s, 3H), 2.12-2.01 (m, 2H), 1.77-1.62(m, 2H);

¹³C NMR (100 MHz, DMSO-d₆): δ 159.11, 158.21, 157.26, 153.81, 145.85,142.40, 137.78, 131.58, 128.82, 126.16, 117.94, 111.63, 108.73, 107.14,104.63, 100.49, 48.68, 44.33, 30.91, 14.81.

Example 286-(4-((5-chloro-2-((2-(difluoromethyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate

To a suspension of 4-bromopyridin-2-amine (6.00 g, 34.7 mmol) in EtOH(100 mL) were added 4-methylbenzenesulfonic acid hydrate (1.32 g, 6.94mmol) and ethyl 3-bromo-2-oxopropanoate (10.14 g, 52.00 mmol). Themixture was placed in a sealed tube, heated to 100° C. and stirredovernight. The mixture was concentrated in vacuo. The residue wasdiluted with saturated Na₂CO₃ aqueous solution (50 mL) and water (30mL), the resulting mixture was extracted with DCM (100 mL×3). Thecombined organic layers was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/10 to 1/5 to 1/2) to get the titlecompound as a light-yellow solid (3.80 g, yield 40%).

MS (ESI, pos. ion) m/z: 269.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.15 (s, 1H), 8.00 (d, J=7.2 Hz, 1H),7.86 (s, 1H), 6.97 (dd, J=7.2, 1.7 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 1.43(t, J=7.1 Hz, 3H).

Step 2) 7-bromoimidazo[1,2-a]pyridine-2-carbaldehyde

To a suspension of ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate(3.50 g, 13.0 mmol) in anhydrous DCM (80 mL) was addeddiisobutylaluminum hydride (18.50 mL, 18.50 mmol, 1.0 M) at 78° C. underN₂ atmosphere. The mixture was stirred at 78° C. overnight and thenmoved to 0° C., and quenched with water (0.75 mL), 15% NaOH aqueoussolution (0.75 mL) and another water (2 mL) successively. The resultingmixture was stirred at rt for 15 min. To the mixture were added Et₂O (50mL), EtOAc (50 mL) and hydrous Mg₂SO₄ (20 g), stirred for 15 min,filtered. The filter cake was washed with EtOAc (200 mL), the filtratewas concentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/10 to 1/5) to afford the title compoundas a light-yellow solid (1.50 g, 51%).

MS (ESI, pos. ion) m/z: 225.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.14 (s, 1H), 8.13 (s, 1H), 8.04 (d,J=7.2 Hz, 1H), 7.89 (s, 1H), 7.02 (dd, J=7.2, 1.7 Hz, 1H).

Step 3) 7-bromo-2-(difluoromethyl)imidazo[1,2-a]pyridine

To a suspension of 7-bromoimidazo[1,2-a]pyridine-2-carbaldehyde (1.45 g,6.44 mmol) in anhydrous DCM (30 mL) was slowly added diethylaminosulfurtrifluoride (8.50 mL, 64.3 mmol). The mixture was stirred at −78° C. for15 min, then moved to room temperature and stirred overnight. Themixture was cooled down to 0° C., and quenched with saturated NaHCO₃aqueous solution (20 mL) and water (50 mL) successively. The resultingmixture was extracted with DCM (50 mL×4). The combined organic layerswas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/10 to 1/5) to get the title compound as a light-yellow solid(0.55 g, yield 35%).

MS (ESI, pos. ion) m/z: 247.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.01 (d, J=7.2 Hz, 1H), 7.83 (s, 1H),7.79 (s, 1H), 6.98 (dd, J=7.2, 1.7 Hz, 1H), 6.84 (t, J=52.0 Hz, 1H).

¹⁹F NMR (376 MHz, CDCl₃) δ (ppm): −114.23.

Step 4)2-(difluoromethyl)-N-(diphenylmethylene)imidazo[1,2-a]pyridin-7-amine

To a suspension of 7-bromo-2-(difluoromethyl)imidazo[1,2-a]pyridine(0.50 g, 2.0 mmol) in anhydrous 1,4-dioxane (20 mL) were added BINAP(0.26 g, 0.416 mmol6), Pd₂(dba)₃ (0.19 g, 0.21 mmol), t-BuONa (0.40 g,4.18 mmol) and diphenylmethanimine (0.74 g, 4.07 mmol). The mixture wasdegassed and refilled with N₂ for several times and heated to 105° C.and stirred overnight. The mixture was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/3 to 1/1) to afford the title compound as brown liquid (0.60 g,yield 85%).

MS (ESI, pos. ion) m/z: 348.2 [M+H]⁺.

Step 5) 2-(difluoromethyl)imidazo[1,2-a]pyridin-7-amine

To a suspension of2-(difluoromethyl)-N-(diphenylmethylene)imidazo[1,2-a]pyridin-7-amine(0.53 g, 1.50 mmol) in DCM (20 mL) was added a solution of HCl in EtOAc(20.0 ml, 60.0 mmol, 3.0 M). The mixture was stirred at room temperaturefor 30 min, then concentrated in vacuo. The residue was diluted with DCM(20 mL) and saturated Na₂CO₃ aqueous solution (20 mL) and the resultingmixture was stirred for 15 min. The organic layer was separated and theaqueous layer was extracted with DCM (50 mL×2) and a mixed solvent ofDCM/MeOH (10/1 (v/v), 50 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by a silica gel column chromatography (DCM/(a solution ofNH₃ in MeOH (3M)) (v/v)=50/1 to 20/1) to afford the title compound as ayellow solid (0.12 g, yield 43%).

MS (ESI, pos. ion) m/z: 184.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (d, J=7.3 Hz, 1H), 7.54 (s, 1H),6.78 (t, J=55.8 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 6.35 (dd, J=7.3, 2.2Hz, 1H), 4.00 (s, 2H);

¹⁹F NMR (376 MHz, CDCl₃) δ (ppm): 113.93.

Step 6)6-(4-((5-chloro-2-((2-(difluoromethyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(0.10 g, 0.29 mmol) in anhydrous 1,4-dioxane (10 mL) were added2-(difluoromethyl)imidazo[1,2-a]pyridin-7-amine (0.064 g, 0.35 mmol),Pd(OAc)₂ (0.016 g, 0.070 mmol), BINAP (0.038 g, 0.061 mmol) and Cs₂CO₃(0.20 g, 0.61 mmol). The mixture was degassed and refilled with N₂ forseveral times and then stirred at 105° C. for 3 h. The mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=100/1 to50/1) to afford a white solid. The solid was stirred with EtOAc (5 mL)for 0.5 hour, filtered and dried in vacuo to afford the title compoundas a white solid (70 mg, 49%).

MS (ESI, pos. ion) m/z: 497.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 497.1550 [M+H]⁺, calculated value forC₂₂H₂₀ClF₂N₁₀ [M+H]⁺ is 497.1524;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.70 (s, 1H), 8.42 (d, J=7.4 Hz, 1H),8.22 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.89 (d, J=9.7 Hz, 1H), 7.45(d, J=9.8 Hz, 1H), 7.21 (dd, J=7.5, 2.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H),7.04 (t, J=52.0 Hz, 1H), 4.71-4.59 (m, 2H), 4.46-4.34 (m, 1H), 3.29-3.20(m, 2H), 2.11-2.02 (m, 2H), 1.76-1.64 (m, 2H);

¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 158.62, 157.62, 156.83, 153.31,146.14, 138.93, 131.12, 129.66, 128.37, 126.93, 117.46, 113.55, 112.01,111.16, 108.63, 104.67, 100.18, 56.02, 48.21, 43.86, 30.41, 18.56;

¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): 112.19.

Example 296-(4-((5-chloro-2-((3,8-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) N-(diphenylmethylene)-3,8-dimethylimidazo[1,2-a]pyridin-7-amine

To a solution of 7-bromo-3,8-dimethylimidazo[1,2-a]pyridine (995 mg,4.4207 mmol), diphenylmethanimine (1.61 g, 8.89 mmol) and t-BuONa (850mg, 8.845 mmol) in 1,4-dioxane (30 mL) were added BINAP (276 mg, 0.4432mmol) and Pd₂(dba)₃ (209 mg, 0.22139 mmol). The mixture was degassed for5 min and refilled with N₂ and stirred at 100° C. for 4 h. The mixturewas concentrated in vacuo and the residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=100/1 to 50/1) to give the titlecompound as a yellow solid (522 mg, yield 36.29%).

MS (ESI, pos. ion) m/z: 326.4 [M+H]⁺.

Step 2) 3,8-dimethylimidazo[1,2-a]pyridin-7-amine

To a solution ofN-(diphenylmethylene)-3,8-dimethylimidazo[1,2-a]pyridin-7-amine (522 mg,1.604 mmol) in DCM (15 mL) was added a solution of hydrogen chloride inEtOAc (16 mL, 48 mmol, 3 M). The reaction mixture was stirred at rt for4 hours and concentrated in vacuo. The residue was dissolved in water(15 mL) and the resulting mixture was adjusted to pH=10 with a saturatedNaHCO₃ aqueous solution, then the mixture was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1 to 20/1) to give the title compound as a yellow solid (234mg, yield 90.49%).

MS (ESI, pos. ion) m/z: 162.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.54 (d, J=7.2 Hz, 1H), 7.18 (s, 1H),6.37 (d, J=7.2 Hz, 1H), 3.77 (s, 2H), 2.38 (s, 6H).

Step 3) tert-butyl4-((5-chloro-2-((3,8-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate

To a solution of 3,8-dimethylimidazo[1,2-a]pyridin-7-amine (175 mg,1.0856 mmol), tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)piperidine-1-carboxylate (415 mg,1.195 mmol) and Cs₂CO₃ (1.06 g, 3.25 mmol) in 1,4-dioxane (20 mL) wereadded Pd(OAc)₂ (25 mg, 0.1114 mmol) and BINAP (68 mg, 0.1092 mmol). Themixture was degassed for 2 min and refilled with N₂ and stirred at 105°C. for 4 h. The mixture was concentrated in vacuo and the residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=50/1 to20/1) to give the title compound as a light yellow solid (438 mg, yield85.48%).

MS (ESI, pos. ion) m/z: 472.2 [M+H]⁺.

Step 4)5-chloro-N²-(3,8-dimethylimidazo[1,2-a]pyridin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-((3,8-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate(438 mg, 0.928 mmol) in DCM (12 mL) was added a solution of hydrogenchloride in EtOAc (6 mL, 18 mmo, 3 M). The reaction mixture was stirredat rt for 2 hours and concentrated in vacuo. The residue was dissolvedin water (20 mL) and the resulting mixture was adjusted to pH=8-9 with asaturated NaHCO₃ aqueous solution, then the mixture was concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=50/1 to 20/1) to give the title compound as an off-whitesolid (256 mg, yield 74.18%).

MS (ESI, pos. ion) m/z: 372.4 [M+H]⁺;

1H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.61 (s, 1H), 7.97 (d, J=7.4 Hz, 1H),7.86 (s, 1H), 7.23 (s, 1H), 7.17 (d, J=7.3 Hz, 1H), 6.68 (d, J=7.9 Hz,1H), 3.95-3.82 (m, 1H), 3.45 (dt, J=29.1, 5.1 Hz, 2H), 2.92 (d, J=12.3Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H), 1.72 (d, J=10.0 Hz, 2H), 1.44 (qd,J=12.0, 3.9 Hz, 2H).

Step 5)6-(4-((5-chloro-2-((3,8-dimethylimidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-vl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of5-chloro-N²-(3,8-dimethylimidazo[1,2-a]pyridin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine(100 mg, 0.2689 mmol) in ethanol (10 mL) were added6-chloropyridazine-3-carbonitrile (56.5 mg, 0.405 mmol) and TEA (54.5mg, 0.539 mmol). The mixture was stirred at room temperature overnight.The mixture was filtered and the filter cake was washed with EtOH (50mL×3) to give the title product as a light yellow solid (98 mg, yield76.73%).

MS(ESI, pos.ion)m/z: 475.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.78 (s, 1H), 8.10 (d, J=7.2 Hz, 1H),7.91 (s, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.38 (t, J=8.7 Hz, 2H), 7.32 (s,1H), 6.89 (d, J=7.7 Hz, 1H), 4.56 (d, J=12.3 Hz, 2H), 4.21 (s, 1H), 3.05(t, J=12.5 Hz, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 1.94 (d, J=11.8 Hz, 2H),1.69-1.53 (m, 2H).

Example 306-(4-((5-chloro-2-((3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 4-bromo-2-hydrazinylpyridine

To a suspension of 4-bromo-2-fluoropyridine (6.00 g, 34.1 mmol) in EtOH(60 mL) was added hydrazine hydrate (21.0 mL, 346 mmol, mass %=80%). Themixture was heated to 75° C. and stirred overnight, then cooled down toroom temperature and quenched with NaOH aqueous solution (25 mL, 4 M)and water (200 mL). The resulting mixture was cooled down to 0° C. andstirred further for 15 min, filtered. The filtrate cake was washed withwater (100 mL), collected and dried in vacuo to afford the titlecompound as a yellow solid (4.60 g, yield 71%).

MS (ESI, pos. ion) m/z: 188.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.92 (d, J=5.4 Hz, 1H), 6.98 (d, J=1.4Hz, 1H), 6.81 (dd, J=5.4, 1.6 Hz, 1H), 5.89 (s, 1H), 3.78 (s, 2H).

Step 2) ethyl 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate

To a suspension of 4-bromo-2-hydrazinylpyridine (4.60 g, 24.5 mmol) inMeOH (60 mL) was added ethyl 2-oxoacetate (5.99 g, 29.3 mmol). Themixture was heated to 60° C. and stirred for 2 h, then cooled down toroom temperature and concentrated in vacuo. The residue was added DCM(60 mL) and cooled down to 0° C., then (diacetoxyiodo)benzene (10.26 g,31.85 mmol) was added in portions. After addition, the mixture was movedto room temperature and stirred overnight. The mixture was diluted inDCM (200 mL), and the resulting mixture was washed with water (50 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/5) to afford the title compound as a white solid (5.10 g, yield77%).

MS (ESI, pos. ion) m/z: 270.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.03 (d, J=7.3 Hz, 1H), 8.14 (s, 1H),7.19 (dd, J=7.4, 1.7 Hz, 1H), 4.58 (q, J=7.1 Hz, 2H), 1.51 (t, J=7.1 Hz,3H).

Step 3) (7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanol

To a suspension of ethyl7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (3.40 g, 12.6 mmol)in anhydrous THF (100.0 mL) was slowly added DIBAL-H (51.0 mL, 51 mmol,1.0 M) at 0° C. The mixture was stirred at 0° C. for another 1.5 h. Themixture was quenched with water (2 mL), 15% NaOH aqueous solution (2mL), water (5 mL) and DCM (200 mL) in turn. The resulting mixture wasmoved to room temperature and stirred for 15 min, then added anhydrousMgSO₄, stirred further for 15 min, filtered. The filter cake was washedwith a mixed solvent of DCM/MeOH (10/1 (v/v), 500 mL×4). The filtratewas concentrated in vacuo and the residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=50/1 to 20/1) to afford the titlecompound as a white solid (1.30 g, yield 45%).

MS (ESI, pos. ion) m/z: 228.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.42 (d, J=7.3 Hz, 1H), 8.16 (d,J=0.7 Hz, 1H), 7.18 (dd, J=7.3, 1.7 Hz, 1H), 5.74 (t, J=5.8 Hz, 1H),4.97 (d, J=5.8 Hz, 2H).

Step 4) 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carbaldehyde

To a suspension of (7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanol(1.30 g, 5.70 mmol) in anhydrous DCM (50 mL) was added dess-martinperiodinane (2.90 g, 6.84 mmol) at 0° C. The mixture was stirred at roomtemperature overnight. The mixture was filtered and the filter cake waswashed with DCM (100 mL). The filtrate was washed with saturated NaHCO₃aqueous solution (60 mL×2), and saturated Na₂S₂O₃ aqueous solution (60mL×2) successively, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=100/1) to afford the title compound as ayellow solid (1.25 g, yield 97%).

MS (ESI, pos. ion) m/z: 226.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 10.25 (s, 1H), 9.05 (d, J=7.2 Hz,1H), 8.56 (d, J=0.9 Hz, 1H), 7.52 (dd, J=7.3, 1.8 Hz, 1H).

Step 5) 7-bromo-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine

To a suspension of 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carbaldehyde(1.28 g, 5.66 mmol) in anhydrous DCM (50 mL) was added DAST (7.50 mL,56.8 mmol) at −78° C. The mixture was stirred at −78° C. for 15 min,then moved to room temperature and stirred overnight. The mixture wascooled down to 0° C., quenched with saturated Na₂CO₃ aqueous solution(10 mL) and water (10 mL). The resulting mixture was stirred for 15 minthen extracted with DCM (50 mL×3) and a mixed solvent of DCM/MeOH (10/1(v/v), 50 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM) to afford the title compound as alight-yellow solid (0.71 g, yield 51%).

MS (ESI, pos. ion) m/z: 248.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.23 (d, J=7.3 Hz, 1H), 8.09 (s, 1H),7.24 (t, J=51.7 Hz, 1H), 7.11 (dd, J=7.0, 1.9 Hz, 1H).

¹⁹F NMR (376 MHz, CDCl₃) δ (ppm): −117.12.

Step 6) 3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine

To a suspension of7-bromo-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (0.71 g, 2.90mmol) in anhydrous 1,4-dioxane (20 mL) were added diphenylmethanimine(1.05 g, 5.79 mmol), Pd₂(dba)₃ (0.26 g, 0.29 mmol), BINAP (0.37 g, 0.59mmol) and t-BuONa (0.56 g, 5.86 mmol). The mixture was degassed andrefilled with N₂ for several times and heated to 105° C. and stirred for3 h. The mixture was concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=50/1 to 30/1 to 20/1) to afford the title compound as a yellowsolid (0.24 g, yield 46%).

MS (ESI, pos. ion) m/z: 185.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.23 (d, J=7.4 Hz, 1H), 7.54 (t,J=51.7 Hz, 1H), 6.65 (dd, J=7.4, 2.0 Hz, 1H), 6.47 (d, J=1.7 Hz, 1H),6.32 (s, 2H);

¹⁹F NMR (376 MHz, DMSO-d6): δ (ppm): −117.09.

Step 7)6-(4-((5-chloro-2-((3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(0.12 g, 0.34 mmol) in anhydrous 1,4-dioxane (10 mL) were added3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine (85 mg, 0.46mmol), Pd(OAc)₂ (22 mg, 0.096 mmol), BINAP (52 mg, 0.0837 mmol) andCs₂CO₃ (0.24 g, 0.73 mmol). The mixture was degassed and refilled withN₂ for several times and heated to 105° C. and stirred overnight. Themixture was concentrated in vacuo. The residue was purified by silicachromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=100/1 to50/1) to afford a yellow solid for 0.11 g. The solid was stirred withMeOH (5 mL) for 1 h, filtered, and the filter cake was collected anddried in vacuo to get the title compound as a light-yellow solid (0.11g, yield 64%).

MS (ESI, pos. ion) m/z: 497.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 497.1536 [M+H]⁺, calculated value forC₂₂H₂₀ClF₂N_(10 [)M+H]⁺ is 497.1524;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.04 (s, 1H), 8.54 (d, J=1.2 Hz,1H), 8.51 (d, J=2.1 Hz, 1H), 8.48 (d, J=7.5 Hz, 1H), 8.12 (s, 1H), 7.86(dd, J=9.1, 2.4 Hz, 1H), 7.65 (t, J=51.7 Hz, 1H), 7.29 (dd, J=7.5, 1.9Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 4.67-4.52 (m,2H), 4.44-4.30 (m, 1H), 3.20-3.09 (m, 2H), 2.08-1.99 (m, 2H), 1.73-1.59(m, 2H);

¹³C NMR (100 MHz, DMSO-d₆): δ 159.43, 157.87, 157.38, 153.81, 153.08,152.65, 141.46, 140.47, 139.28, 124.29, 119.22, 111.94, 109.89, 106.99,105.88, 96.48, 95.36, 49.19, 44.30, 30.98;

¹⁹F NMR (376 MHz, DMSO-d₆) δ (ppm): −117.42.

Example 316-(4-((5-chloro-2-((2,3-dimethylimidazo[1,2-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 6-bromo-2,3-dimethylimidazo[1,2-a]pyridine

To a suspension of 5-bromopyridin-2-amine (4.00 g, 23.12 mmol) in EtOH(60 mL) were added 3-bromobutan-2-one (10.0 mL, 95.4 mmol) and4-methylbenzenesulfonic acid hydrate (0.89 g, 4.68 mmol). The mixturewas placed in a sealed tube, and heated to 100° C. and stirredovernight. The mixture was concentrated in vacuo. The residue wasdiluted with water (50 mL) and DCM (100 mL), and the resulting mixturewas adjusted to pH=10 with NaOH (2M) aqueous solution, then extractedwith DCM (100 mL×5). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/5to 1/2) to afford the title compound as a yellow solid (1.43 g, yield28%).

MS (ESI, pos. ion) m/z: 225.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.92 (d, J=0.9 Hz, 1H), 7.39 (d, J=9.4Hz, 1H), 7.15 (dd, J=9.4, 1.8 Hz, 1H), 2.41 (s, 3H), 2.38 (s, 3H).

Step 2) N-(diphenylmethylene)-2,3-dimethylimidazo[1,2-a]pyridin-6-amine

To a suspension of 6-bromo-2,3-dimethylimidazo[1,2-a]pyridine (1.40 g,6.22 mmol) in anhydrous 1,4-dioxane (40 mL) were addeddiphenylmethanimine (2.25 g, 12.4 mmol), Pd₂(dba)₃ (0.58 g, 0.63 mmol),BINAP (0.78 g, 1.25 mmol) and t-BuONa (1.21 g, 12.59 mmol). The mixturewas degassed and refilled with N2 for several times and heated to 105°C. and stirred overnight. The mixture was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/10 to DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=2/1) to affordthe title compound as a brown liquid (2.03 g, yield 100%).

MS (ESI, pos. ion) m/z: 326.3 [M+H]⁺.

Step 3) 2,3-dimethylimidazo[1,2-a]pyridin-6-amine

To a suspension ofN-(diphenylmethylene)-2,3-dimethylimidazo[1,2-a]pyridin-6-amine (2.03 g,6.24 mmol) in DCM (50 mL) was added a solution of HCl in EtOAc (60 mL,180 mmol, 3 M). The mixture was stirred at room temperature for 30 min.The mixture was concentrated in vacuo. The residue was diluted with DCM(50 mL) and water (30 mL), and the resulting mixture was adjusted topH=10 with 10% NaOH aqueous solution. The organic layer was separatedand the aqueous layer was extracted with DCM (50 mL×5) and a mixedsolvent of DCM/MeOH (10/1 (v/v), 100 mL×2). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (DCM/(asolution of NH₃ in MeOH (3M)) (v/v)=100/1 to 50/1) to afford the titlecompound as a brown solid (0.50 g, yield 50%).

MS (ESI, pos. ion) m/z: 162.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.29 (d, J=1.4 Hz, 1H), 7.18 (d,J=9.4 Hz, 1H), 6.74 (dd, J=9.4, 2.0 Hz, 1H), 4.77 (s, 2H), 2.25 (s, 3H),2.23 (s, 3H).

Step 4)6-(4-((5-chloro-2-((2,3-dimethylimidazo[1,2-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(105 mg, 0.30 mmol) in dried 1,4-dioxane (10 mL) were added2,3-dimethylimidazo[1,2-a]pyridin-6-amine (75 mg, 0.47 mmol), Pd(OAc)₂(14 mg, 0.062 mmol), BIANP (37 mg, 0.060 mmol) and Cs₂CO₃ (0.22 g, 0.69mmol). The mixture was degassed and refilled with N₂ for several timesand heated to 105° C. and stirred for 3 h. The mixture was concentratedin vacuo and the residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (3M)) (v/v)=100/1 to50/1) to get a light green solid for 0.11 g. The solid was purifiedfurther by preparative TLC (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=30/1) to afford the title compound as a light green solid (55 mg,yield 39%).

MS (ESI, pos. ion) m/z: 474.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 474.1925 [M+H]⁺, calculated value forC₂₄H₂₅ClN₉ [M+H]⁺ is 474.1916;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.55 (s, 1H), 8.41 (d, J=2.1 Hz, 1H),7.97 (s, 1H), 7.62 (dd, J=9.0, 2.3 Hz, 1H), 7.51 (d, J=9.5 Hz, 1H), 7.08(dd, J=9.4, 1.3 Hz, 1H), 6.80 (s, 1H), 6.64 (d, J=9.0 Hz, 1H), 5.16 (d,J=7.6 Hz, 1H), 4.42-4.33 (m, 2H), 4.31-4.20 (m, 1H), 3.22-3.13 (m, 2H),2.43 (s, 3H), 2.41 (s, 3H), 2.20-2.12 (m, 2H), 1.60-1.51 (m, 2H);

¹³C NMR (100 MHz, CDCl₃) δ (ppm): 159.04, 158.18, 157.11, 153.17,152.79, 139.99, 126.96, 120.63, 118.58, 116.42, 115.78, 113.47, 105.78,105.59, 96.47, 77.24, 77.03, 76.82, 47.90, 43.55, 31.58, 13.08, 8.63.

Example 326-(4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) tert-butyl (mesitylsulfonyl)oxycarbamate

To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (54.98 g,251.4 mmol) and tert-butyl hydroxycarbamate (33.44 g, 251.1 mmol) inEtOAc (100 mL) was added Et₃N (32.27 g, 318.9 mmol) dropwise at −10° C.After addition, the reaction mixture was warmed to 0° C. and stirred for1 h, then quenched with water (100 mL), and extracted with EtOAc (100mL×3). The combined organic phases were washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe title compound as a yellow solid (73.01 g, yield 92.1%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.63 (s, 1H), 7.01 (s, 2H), 2.70 (s,6H), 2.34 (s, 3H), 1.34 (s, 9H).

Step 2) 1,2-diamino-4-bromopyridin-1-ium 2,4,6-trimethylbenzenesulfonate

Trifluoroacetic acid (200 mL) was cooled at 0° C. and added totert-butyl (mesitylsulfonyl)oxycarbamate (55.18 g, 175.0 mmol) dropwiseat 0° C. After addition, the reaction mixture was stirred at 0° C. for2.5 h, and then quenched with water (400 mL) and extracted with DCM (400mL). The organic phase was cooled down to 0° C. and4-bromopyridin-2-amine (30.33 g, 175.3 mmol) was added portionwise.After addition, the reaction mixture was stirred at 0° C. for further 1hour and filtered. The filter cake was washed with Et₂O (50 mL×2) togive the title compound as a white solid (67.94 g, yield 100%).

MS (ESI, pos. ion) m/z: 188.0 [C₅H₇BrN₃]⁺.

Step 3) 7-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 1,2-diamino-4-bromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (67.94 g, 175.0 mmol) and acetyl acetate(71.53 g, 700.7 mmol) in EtOH (200 mL) was added 4-methylbenzenesulfonicacid hydrate (6.67 g, 35.1 mmol). After addition, the reaction mixturewas placed in a sealed tube and stirred at 100° C. for 24 h, then cooleddown to rt, and quenched with water (100 mL). The resulting mixture wasadjusted to pH=10 with a saturated Na₂CO₃ aqueous solution, thenextracted with DCM (500 mL×3). The combined organic phases were washedwith brine (500 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/14) to give the title compound as ayellow solid (2.14 g, yield 5.8%).

MS (ESI, pos. ion) m/z: 212.1 [M+H]⁺.

Step 4)N-(diphenylmethylene)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine

To a solution of 7-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (2.14g, 10.09 mmol) and diphenylmethanimine (2.75 g, 15.17 mmol) in1,4-dioxane (40 mL) were added Pd₂(dba)₃ (467.0 mg, 0.51 mmol), BINAP(95%, 664.4 mg, 1.01 mmol) and t-BuONa (1.94 g, 20.19 mmol). Thereaction mixture was stirred at 100° C. overnight, then cooled down tort and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (MeOH/DCM (v/v)=1/10) to give the title compoundas a yellow solid (2.56 g, yield 81.2%).

MS (ESI, pos. ion) m/z: 313.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.23 (d, J=7.2 Hz, 1H), 7.78 (d, J=7.4Hz, 2H), 7.54 (t, J=6.3 Hz, 1H), 7.45 (t, J=7.3 Hz, 2H), 7.31 (d, J=7.0Hz, 3H), 7.17 (d, J=6.3 Hz, 2H), 6.85 (s, 1H), 6.45 (dd, J=7.2, 2.0 Hz,1H), 2.53 (s, 3H).

Step 5) 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine

To a solution ofN-(diphenylmethylene)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine(2.56 g, 8.19 mmol) in 1,4-dioxane (80 mL) was added a solution of HClin water (80 mL, 320 mmol, 4 M) dropwise. The reaction mixture wasstirred at rt overnight and adjusted to pH=10 with Na₂CO₃ powder, thenextracted with DCM (250 mL×9). The combined organic phases wereconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as brownoil (560.1 mg, yield 46.1%).

MS (ESI, pos. ion) m/z: 149.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.19 (d, J=7.3 Hz, 1H), 6.66 (d, J=2.3Hz, 1H), 6.36 (dd, J=7.3, 2.3 Hz, 1H), 4.16 (s, 2H), 2.52 (s, 3H).

Step 6) tert-butyl4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate

To a suspension of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)piperidine-1-carboxylate (967.7 mg,2.79 mmol) and 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (410.2 mg,2.77 mmol) in 1,4-dioxane (40 mL) were added Pd(OAc)₂ (129.6 mg, 0.58mmol), BINAP (98%, 362.4 mg, 0.57 mmol) and Cs₂CO₃ (98%, 1.84 g, 5.53mmol). The reaction mixture was stirred at 100° C. overnight andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=3/1) to give the title compound as a paleyellow solid (567.5 mg, yield 44.4%).

MS (ESI, pos. ion) m/z: 459.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.30 (d, J=7.4 Hz, 1H), 8.13 (s, 1H),7.95 (s, 1H), 7.63 (s, 1H), 7.02 (d, J=6.9 Hz, 1H), 5.26 (d, J=7.3 Hz,1H), 4.22-4.14 (m, 1H), 4.09 (s, 2H), 3.08 (s, 2H), 2.55 (s, 3H),2.15-2.07 (s, 2H), 1.52-1.45 (m, 11H).

Step 7)5-chloro-N²-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate (207.3 mg, 0.45mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40mmol, 4 M). The reaction mixture was stirred at rt for 0.5 hour andconcentrated in vacuo. The residue was dissolved in water (10 mL) andthe resulting mixture was adjusted to pH=10 with a saturated Na₂CO₃aqueous solution, then extracted with DCM (100 mL×3). The combinedorganic phases were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the titlecompound as a pale yellow solid (162.1 mg, yield 100%).

MS (ESI, pos. ion) m/z: 359.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.30 (d, J=7.4 Hz, 1H), 8.07 (d, J=1.9Hz, 1H), 7.96 (s, 1H), 7.14 (s, 1H), 7.08 (dd, J=7.4, 2.1 Hz, 1H), 5.26(d, J=7.4 Hz, 1H), 4.17-4.03 (m, 1H), 3.49 (s, 1H), 3.16 (dt, J=6.1, 3.5Hz, 2H), 2.91-2.80 (m, 2H), 2.55 (s, 3H), 2.12 (dd, J=11.5, 2.1 Hz, 2H),1.49 (dd, J=11.9, 3.4 Hz, 2H).

Step 8)6-(4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of5-chloro-N²-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine(143.7 mg, 0.40 mmol) and Et₃N (135.2 mg, 1.34 mmol) in EtOH (20 mL) wasadded 6-chloronicotinonitrile (112.4 mg, 0.81 mmol). The reactionmixture was stirred at rt overnight, then quenched with water (30 mL),and extracted with DCM (100 mL×3). The combined organic phases werewashed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/40) to give the title compound as abeige solid (127.3 mg, yield 69.0%).

MS (ESI, pos. ion) m/z: 461.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 461.1694 [M+H]⁺, calculated value forC₂₂H₂₂ClN₁₀ [M+H]⁺ is 461.1717;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.87 (s, 1H), 8.62 (d, J=7.0 Hz, 1H),8.51 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.26(d, J=6.5 Hz, 1H), 7.12 (d, J=6.7 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 4.56(d, J=11.7 Hz, 2H), 4.36 (s, 1H), 3.14 (t, J=12.1 Hz, 2H), 2.37 (s, 3H),2.01 (d, J=10.3 Hz, 2H), 1.72-1.56 (m, 2H);

¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 163.5, 159.4, 157.9, 157.3, 153.8,153.1, 152.3, 142.5, 140.5, 128.2, 119.3, 108.0, 107.0, 105.5, 98.7,95.3, 49.0, 44.3, 31.0, 14.7.

Example 336-(4-((5-chloro-2-((2-methylimidazo[1,2-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 2-methylimidazo[1,2-b]pyridazin-7-amine

To a solution of pyridazine-3,5-diamine (509 mg, 4.62 mmol) in EtOH (20mL) were added 4-methylbenzenesulfonic acid (156 mg, 0.905 mmol) and1-bromopropan-2-one (1.56 g, 11.4 mmol). The reaction mixture wasstirred at 100° C. overnight and concentrated in vacuo. The residue waspurified by silica gel column chromatography (a solution of NH₃ in MeOH(7M))/DCM(v/v)=1/30) to give the title compound as a yellow solid (467mg, yield 68.2%).

MS (ESI, pos. ion) m/z: 149.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.41 (d, J=1.9 Hz, 1H), 7.94 (s, 1H),7.25 (s, 2H), 6.89 (s, H), 2.35 (s, 3H).

Step 2)6-(4-((5-chloro-2-((2-methylimidazo[1,2-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(101 mg, 0.288 mmol) and 2-methylimidazo[1,2-b]pyridazin-7-amine (65 mg,0.438 mmol) in 1,4-dioxane (15 mL) were added BINAP (36 mg, 0.057 mmol),Cs₂CO₃ (189 mg, 0.580 mmol) and Pd(OAc)₂ (13 mg, 0.057 mmol). Themixture was stirred at 105° C. overnight and concentrated in vacuo. Theresidue was purified by silica gel column chromatography ((MeOH/DCM(v/v)=1/30) to give the title compound as a yellow solid (55 mg, yield41.3%).

MS (ESI, pos. ion) m/z: 462.4 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 462.1666 [M+H]⁺, calculated value forC₂₁H₂₁ClN₁₁ [M+H]⁺ is 462.1592;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.84 (s, 1H), 8.60 (s, 1H), 8.43 (s,1H), 8.08 (s, 1H), 7.88 (d, J=9.4 Hz, 1H), 7.81 (s, 1H), 7.45 (d, J=9.4Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 4.63 (s, 2H), 4.36 (s, 1H), 3.22 (t,J=12.3 Hz, 2H), 2.31 (s, 3H), 2.04 (d, J=10.8 Hz, 2H), 1.69 (d, J=10.8Hz, 2H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 158.62, 157.53, 156.88, 153.32,141.88, 138.76, 138.39, 131.75, 131.12, 128.38, 117.46, 112.00, 111.19,106.11, 105.00, 48.21, 43.82, 30.38, 14.41.

Example 346-(4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) tert-butyl (mesitylsulfonyl)oxycarbamate

To a solution of 2,4,6-trimethylbenzene-1-sulfonylchloride (54.98 g,251.4 mmol) and tert-butyl hydroxycarbamate (33.44 g, 251.1 mmol) inEtOAc (100 mL) at 10° C. was slowly added Et₃N (32.27 g, 318.9 mmol).After addition, the reaction mixture was warmed to 0° C. and stirred for1 h, quenched with water (100 mL), and the resulting mixture wasextracted with EtOAc (100 mL×3). The combined organic phases were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound as a yellow solid(73.01 g, yield 92.1%).

¹HNMR (400 MHz, CDCl₃) δ (ppm): 7.63 (s, 1H), 7.01 (s, 2H), 2.70 (s,6H), 2.34 (s, 3H), 1.34 (s, 9H).

Step 2) O-(mesitylsulfonyl)hydroxylamine

At 0° C., to the solid of tert-butyl(mesitylsulfonyl)oxycarbamate (29.00g, 91.95 mmol) was added 2,2,2-trifluoroacetic acid (60 mL) cooling inadvance. The mixture stirred at 0° C. overnight and then quenched withwater (180 mL), the resulting mixture was extracted with DCM (250 mL).The organic layer was used directly for next step without furtherpurification.

Step 3) (1,2-diamino-5-bromopyridin-1-ium)2,4,6-trimethylbenzenesulfonate

The solution of O-(mesitylsulfonyl)hydroxylamine in DCM obtained fromprevious step was cooled down to 0° C., and then 5-bromopyridin-2-amine(5.00 g, 28.9 mmol) was added. The mixture was stirred at 0° C. for 1hour and then concentrated in vacuo to afford a light-yellow stickyliquid for 11.2 g (yield for steps 2) to step 3) 100%). The crudeproduct was used for next step directly without further purification.

Step 4) 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine

To a suspension of(1,2-diamino-5-bromopyridin-1-ium)2,4,6-trimethylbenzenesulfonate (13.47g, 34.69 mmol) in Ac₂O (70 mL) was added 4-methylbenzenesulfonic acidhydrate (1.37 g, 7.21 mmol). The mixture was placed in a sealed tube andheated to 110° C. and stirred for 24 h. The mixture was quenched withwater (30 mL), then concentrated in vacuo. The residue was diluted withwater (50 mL), and the resulting mixture was adjusted to pH=10 withsaturated Na₂CO₃ aqueous solution and then extracted with EtOAc (200mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc/PE (v/v)=1/10 to 1/5) to afford thecrude product as a yellow solid (3.90 g). The crude product wasdissolved in DCM (50 mL), then triethyloxonium tetrafluoroborate (22.0mL, 22 mmol, 1.0 M) was added to the resulting solution. The resultingmixture was stirred at room temperature overnight, then filtered and thefilter cake was washed with DCM (50 mL). The filtrate was washed withsaturated Na₂CO₃ aqueous solution (50.0 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to afford the title compoundas a yellow solid (0.85 g, yield 12%).

MS (ESI, pos. ion) m/z: 212.0 [M+H]⁺.

Step 5)N-(diphenylmethylene)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine

To a suspension of 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.84g, 4.00 mmol) in anhydrous 1,4-dioxane (20 mL) were added Pd₂(dba)₃(0.36 g, 0.40 mmol), BINAP (0.49 g, 0.79 mmol), diphenylmethanimine(1.45 g, 8.02 mmol) and t-BuONa (0.77 g, 8.01 mmol). The mixture wasdegassed and refilled with N₂ for several times and heated to 105° C.and stirred overnight. The mixture was concentrated in vacuo and theresidue was purified by silica chromatography (EtOAc/PE (v/v)=1/2 to 1/1to EtOAc 100%) to afford the title compound as brown liquid (0.34 g,yield 27%).

MS (ESI, pos. ion) m/z: 313.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.97-7.92 (m, 1H), 7.76 (d, J=7.5 Hz,2H), 7.51 (t, J=7.3 Hz, 1H), 7.47-7.37 (m, 3H), 7.36-7.28 (m, 3H), 7.14(dd, J=7.4, 1.7 Hz, 2H), 6.99 (dd, J=9.3, 1.8 Hz, 1H), 2.53 (s, 3H).

Step 6) 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine

To a suspension ofN-(diphenylmethylene)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine(0.34 g, 1.10 mmol) in 1,4-dioxnae (10 mL) was added hydrochloric acid(10 mL, 40 mmol, 4.0 M). The mixture was stirred at room temperatureovernight and then adjusted to pH=10 with saturated Na₂CO₃ aqueoussolution and extracted with DCM (50 mL×3) and a mixed solvent ofDCM/MeOH (10/1 (v/v), 50 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica gel column chromatography (DCM/(a solution of NH₃in MeOH (3M)) (v/v)=50/1 to 30/1) to afford the title compound as alight-yellow solid (50 mg, yield 31%).

MS (ESI, pos. ion) m/z: 149.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.93 (d, J=1.9 Hz, 1H), 7.42 (d,J=9.4 Hz, 1H), 7.12 (dd, J=9.4, 2.1 Hz, 1H), 5.13 (s, 2H), 2.36 (s, 3H).

Step 7)6-(4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(0.11 g, 0.32 mmol) in 1,4-dioxane (10 mL) were added2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (54 mg, 0.36 mmol),Pd(OAc)₂ (16 mg, 0.072 mmol), BINAP (40 mg, 0.065 mmol) and Cs₂CO₃ (0.21g, 0.64 mmol. The mixture was degassed and refilled with N₂ for severaltimes and heated to 105° C. and stirred for 3 hours and thenconcentrated in vacuo. The residue was diluted with DCM (20 mL) andwater (20 mL), and the resulting mixture was stirred for 10 min. Theorganic layer was separated and the aqueous layer was extracted with DCM(50 mL×2). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=50/1 to 30/1) to get the crude product. The crude product waspurified further by preparative TLC (DCM/(a solution of NH₃ in MeOH(3M)) (v/v)=20/1) to afford the title compound as a gray solid (45 mg,yield 30%).

MS (ESI, pos. ion) m/z: 462.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 462.1658 [M+H]⁺, calculated value forC₂₁H₂₁ClN₁₁ [M+H]⁺ is 462.1664;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 9.48 (s, 1H), 7.97 (s, 1H), 7.55 (d,J=9.4 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H), 7.31-7.27 (m, 1H), 6.99 (s, 1H),6.90 (d, J=9.6 Hz, 1H), 5.24 (d, J=7.2 Hz, 1H), 4.64-4.53 (m, 2H),4.40-4.30 (m, 1H), 3.45-3.36 (m, 2H), 2.55 (s, 3H), 2.35-2.27 (m, 2H),1.67-1.64 (m, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 163.75, 158.35, 157.41, 157.18,153.25, 147.92, 130.72, 129.26, 128.15, 124.93, 118.05, 116.79, 115.02,109.82, 105.73, 48.45, 43.76, 31.52, 14.50.

Example 356-(4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) O-(mesitylsulfonyl)hydroxylamine

2,2,2-trifluoroacetic acid (60 mL) was cooled to 0° C. andtert-butyl(mesitylsulfonyl) oxycarbamate (29.00 g, 91.95 mmol) was addedportionwise. The mixture was stirred at 0° C. overnight and thenquenched with water (180 mL). The separated aqueous layer was extractedwith DCM (90 mL×2) and the combined organic layers were used in the nextstep without further purification.

Step 2) 1,2-diamino-4-bromopyridin-1-ium 2,4,6-trimethylbenzenesulfonate

To the solution of O-(mesitylsulfonyl)hydroxylamine in DCM (180 mL)obtained from the previous step was added 4-bromopyridin-2-amine (6.00g, 34.7 mmol) at 0° C., and the reaction mixture was stirred for 1 h.The mixture was concentrated in vacuo to afford the crude product as awhite solid (13.50 g), which was used directly in the next step withoutfurther purification.

MS (ESI, pos. ion) m/z: 188.1, 190.1 [M₁]⁺;

MS (ESI, neg. ion) m/z: 199.1 [M₂]⁻.

Step 3) 7-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 1,2-diamino-4-bromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (13.00 g, 33.48 mmol) in aceticanhydride (50 mL) was added 4-methylbenzenesulfonic acid (1.30 g, 7.55mmol). The mixture was placed in a sealed tube and stirred at 100° C.overnight and then quenched with water (200 mL). The resulting mixturewas adjusted to pH=9 with NaOH aqueous solution (1 M), and extractedwith DCM (80 mL×3). The combined organic layers were washed with brine(100 mL×2), dried over anhydrous Na₂SO₄, filtrated, and concentrated invacuo. The residue was purified by silica gel column chromatography(EtOAc/PE (v/v)=1/10 to 1/6) to afford the title compound as a whitesolid (4.90 g, yield 69.0% for 3 step 1) to 3)).

MS (ESI, pos. ion) m/z: 212.0 [M+H]⁺.

Step 4)N-(diphenylmethylene)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine

To a solution of 7-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (4.40g, 20.7 mmol) and diphenylmethanimine (5.64 g, 31.1 mmol) in 1,4-dioxane(60 mL) were added Pd₂(dba)₃ (952.2 mg, 1.04 mmol), BINAP (1.29 g, 2.07mmol) and Cs₂CO₃ (13.52 g, 41.50 mmol). The mixture was stirred at 100°C. for 4 hours under N₂ atmosphere, and concentrated in vacuo. Theresidue was diluted with water (200 mL) and DCM (100 mL), and theseparated aqueous layer was extracted with DCM (100 mL×2). The combinedorganic layers were washed with water (100 mL×2), and concentrated invacuo. The residue was purified by silica gel column chromatography(EtOAc/PE (v/v)=1/5 to 1/2) to give the title compound as brown oil(6.48 g, yield 100%).

MS (ESI, pos. ion) m/z: 313.1 [M+H]⁺.

Step 5) 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine

To a solution ofN-(diphenylmethylene)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine(6.48 g, 20.7 mmol) in DCM (25 mL) was added a solution of HCl in EtOAc(80 mL, 240 mmol, 3 M). The reaction mixture was stirred at rt overnightat room temperature and concentrated in vacuo. The residue was dilutedwith water (100 mL), and the resulting mixture was adjusted to pH=9 withNaOH aqueous solution (1 M), and then extracted with DCM (50 mL×3). Thecombined organic layers were concentrated in vacuo and the residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/200 to1/30) to give the title compound as a yellow solid (1.45 g, yield47.2%).

MS (ESI, pos. ion) m/z: 149.2 [M+H]⁺.

Step 6) tert-butyl4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate

To a solution of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)piperidine-1-carboxylate (1.50 g,4.32 mmol) and 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (641.2 mg,4.33 mmol) in 1,4-dioxane (30 mL) were added Cs₂CO₃ (2.82 g, 8.66 mmol),Pd(OAc)₂ (195.4 mg, 0.87 mmol) and BINAP (536.2 mg, 0.86 mmol). Thereaction mixture was stirred at 100° C. under N₂ atmosphere overnightand then concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (EtOAc/PE (v/v)=1/2 to 3/1) to give the titlecompound as a yellow solid (1.36 g, yield 68.6%).

MS (ESI, pos. ion) m/z: 459.3 [M+H]⁺.

Step 7)5-chloro-N²-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate(1.36 g, 2.96 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc(30 mL, 90 mmol, 3 M). The mixture was stirred at room temperature for 1hour and then concentrated in vacuo. The residue was diluted with water(10 mL), and the resulting mixture was adjusted to pH=9 with NaOHaqueous solution (1 M) and then extracted with DCM (25 mL×3). Thecombined organic layers were concentrated in vacuo and the residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/20 to (asolution of NH₃ in MeOH (7M))/DCM (v/v)=1/10) to give the title productas a yellow solid (613.4 mg, 57.7%).

MS (ESI, pos. ion) m/z: 359.2 [M+H]⁺.

Step 8)6-(4-((5-chloro-2-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of5-chloro-N²-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N⁴-(4-piperidyl)pyrimidine-2,4-diamine(300.2 mg, 0.84 mmol) and 6-chloropyridazine-3-carbonitrile (118.1 mg,0.85 mmol) in methanol (15 mL) was added TEA (129.2 mg, 1.28 mmol). Themixture was stirred at room temperature overnight and then concentratedin vacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/50) to afford the desired product as a yellow solid(146.4 mg, yield 37.9%).

MS (ESI, pos. ion) m/z: 462.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 462.1673 [M+H]⁺, calculated value forC₂₁H₂₁ClN₁₁ [M+H]⁺ is 462.1664;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.84 (s, 1H), 8.54 (d, J=7.4 Hz, 1H),7.99 (s, 1H), 7.51-7.46 (m, 2H), 6.98 (d, J=9.6 Hz, 1H), 6.48 (d, J=7.0Hz, 1H), 4.73-4.63 (m, 1H), 4.46 (d, J=13.4 Hz, 2H), 3.45 (t, J=11.7 Hz,2H), 2.71 (s, 3H), 2.37-2.29 (m, 2H), 1.71 (dt, J=14.6, 7.3 Hz, 2H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 161.6, 158.6, 158.2, 157.2, 151.8,145.4, 144.8, 141.5, 131.0, 129.7, 116.3, 112.5, 111.0, 107.4, 98.7,49.8, 43.1, 30.6, 11.9.

Example 366-(4-((5-chloro-2-((3-methylimidazo[1,2-c]pyrimidin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) pyrimidine-4,6-diamine

A mixture of 6-bromopyrimidin-4-amine (1.01 g, 5.80 mmol) and ammoniasolution (25 mL) was stirred in a sealed tube at 125° C. overnight, thencooled down to rt and concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/15) to give the titlecompound as a yellow solid (0.46 g, yield 72%).

MS (ESI, pos. ion) m/z: 111.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.82 (s, 1H), 6.10 (s, 4H), 5.39 (s,1H).

Step 2) 3-methylimidazo[1,2-c]pyrimidin-7-amine

To a suspension of pyrimidine-4,6-diamine (342.0 mg, 3.10 mmol) andNaHCO₃ (286.0 mg, 3.40 mmol) in EtOH (20 mL) was added a solution of2-chloropropanal (0.57 M, 57 mmol) in a mixed solvent of chloroform andhexane (1/2 (v/v), 100 mL). The reaction mixture was stirred in a sealedtube at 85° C. overnight, then cooled down to rt and concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/20) to give the title compound as brown oil (80.0 mg,yield 17.4%).

MS (ESI, pos. ion) m/z: 149.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.84 (s, 1H), 7.09 (s, 1H), 6.46 (s,2H), 6.26 (s, 1H), 2.40 (s, 3H).

Step 3) tert-butyl4-((5-chloro-2-((3-methylimidazo[1,2-c]pyrimidin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate

To a suspension of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)piperidine-1-carboxylate (451.8 mg,1.30 mmol) and 3-methylimidazo[1,2-c]pyrimidin-7-amine (190.4 mg, 1.28mmol) in 1,4-dioxane (40 mL) were added Pd(OAc)₂ (59.5 mg, 0.26 mmol),BINAP (98%, 172.4 mg, 0.27 mmol) and Cs₂CO₃ (98%, 866.8 mg, 2.61 mmol).The reaction mixture was stirred at 100° C. overnight and concentratedin vacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/40) to give the title compound as a yellow solid (60.5mg, yield 10.1%).

MS (ESI, pos. ion) m/z: 459.2 [M+H]⁺.

Step 4)5-chloro-N²-(3-methylimidazo[1,2-c]pyrimidin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine

To a solution of tert-butyl4-((5-chloro-2-((3-methylimidazo[1,2-c]pyrimidin-7-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate (54.9 mg, 0.12 mmol)in DCM (5 mL) was added a solution of HCl in EtOAc (5 mL, 20 mmol). Thereaction mixture was stirred at rt for 0.5 hour and then concentrated invacuo. The residue was dissolved in water (10 mL) and adjusted to pH=10with a saturated Na₂CO₃ aqueous solution, then extracted with DCM (100mL×3). The combined organic phases were washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/5) to give the title compound as a pale yellow solid (30.4 mg,yield 70.8%).

MS (ESI, pos. ion) m/z: 359.2 [M+H]⁺.

Step 5)6-(4-((5-chloro-2-((3-methylimidazo[1,2-c]pyrimidin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of5-chloro-N²-(3-methylimidazo[1,2-c]pyrimidin-7-yl)-N⁴-(piperidin-4-yl)pyrimidine-2,4-diamine(30.4 mg, 0.085 mmol) and Et₃N (135.2 mg, 1.34 mmol) in EtOH (10 mL) wasadded 6-chloropyridazine-3-carbonitrile (24.2 mg, 0.173 mmol). Thereaction mixture was stirred at rt overnight, then quenched with water(30 mL), and extracted with DCM (50 mL×3). The combined organic phaseswere washed with brine (50 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as abeige solid (27.7 mg, yield 70.8%).

MS (ESI, pos. ion) m/z: 462.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 462.1666 [M+H]⁺, calculated value forC₂₁H₂₁ClN₁₁ [M+H]⁺ is 462.1670;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.58 (s, 1H), 9.14 (s, 1H), 8.12 (d,J=13.9 Hz, 2H), 7.90 (s, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 6.65 (s, 1H),5.47 (s, 1H), 5.33 (s, 2H), 4.64 (s, 2H), 2.27 (s, 3H), 1.72 (s, 2H),1.45 (s, 2H);

¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 174.8, 160.1, 159.0, 157.3, 153.6,146.4, 139.2, 131.6, 130.1, 128.8, 117.9, 111.7, 106.9, 93.3, 48.9,44.3, 35.6, 25.6.

Example 376-(4-((5-chloro-2-((2-methylimidazo[1,2-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(201 mg, 0.575 mmol) and 2-methylimidazo[1,2-b]pyridazin-7-amine (135mg, 0.911 mmol) in 1,4-dioxane (20 mL) were added BINAP (72 mg, 0.115mmol), Cs₂CO₃ (375 mg, 1.15 mmol) and Pd(OAc)₂ (26 mg, 0.115 mmol). Themixture was stirred at 105° C. overnight and concentrated in vacuo. Theresidue was purified by silica gel column chromatography ((MeOH/DCM(v/v)=1/30) to give the title compound as a yellow solid (112 mg, yield42.2%).

MS (ESI, pos. ion) m/z: 461.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 461.1722 [M+H]⁺, calculated value forC₂₂H₂₂ClN₁₀ [M+H]⁺ is 461.1639;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.81 (s, 1H), 8.59 (d, J=2.2 Hz, 1H),8.50 (d, J=2.1 Hz, 1H), 8.43 (s, 1H), 8.06 (s, 1H), 7.85 (dd, J=9.1, 2.3Hz, 1H), 7.79 (s, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.02 (d, J=9.1 Hz, 1H),4.55 (d, J=12.3 Hz, 2H), 4.36-4.29 (m, 1H), 3.11 (t, J=12.5 Hz, 2H),2.30 (s, 3H), 1.99 (d, J=13.5 Hz, 2H), 1.67-1.60 (m, 2H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 158.88, 157.50, 156.82, 153.21,152.54, 142.14, 139.92, 138.78, 138.23, 131.50, 118.68, 111.84, 106.45,106.34, 104.88, 94.81, 48.36, 43.73, 30.41, 14.44.

Example 386-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) ethyl 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetate

To a solution of 4-bromopyridin-2-amine (8.00 g, 46.2 mmol) in ethanol(100 mL) was added ethyl 4-bromo-3-oxo-butanoate (23.22 g, 111.1 mmol),and the reaction mixture was heated to reflux and stirred overnight. Themixture was concentrated in vacuo and the residue was diluted with water(50 mL). The resulting mixture was adjusted to pH=10 with saturatedNa₂CO₃ aqueous solution, and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/5 to 1/2)to afford the title compound as a yellow solid (3.02 g, yield 23%).

MS (ESI, pos. ion) m/z: 283.0 [M+H]⁺.

Step 2) 1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of ethyl 2-(7-bromoimidazo[1,2-a]pyridin-2-ypacetate (2.45g, 8.65 mmol) in tetrahydrofuran (50 mL) was added methylmagnesiumbromide (3.0 M in diethyl ether, 28.8 mL, 86.4 mmol) dropwise under N₂atmosphere at −78° C. The mixture was moved to 0° C. and stirredovernight. The reaction was quenched with water (80 mL), and extractedwith EtOAc (40 mL×3). The combined organic layers were concentrated invacuo, and the residue was purified by silica gel column chromatography(EtOAc/PE (v/v)=1/1 to 2/1) to afford the title compound as a claybanksolid (0.45 g, yield 19%).

MS (ESI, pos. ion) m/z: 269.0 [M+H]⁺.

Step 3)1-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol (450.0 mg,1.67 mmol) and diphenylmethanimine (457.2 mg, 2.52 mmol) in 1,4-dioxane(15 mL) were added Pd₂(dba)₃ (154.4 mg, 0.17 mmol), BINAP (105.1 mg,0.17 mmol) and Cs₂CO₃ (1.09 g, 3.35 mmol). The mixture was stirred at100° C. for 6 hours under N₂ atmosphere. The mixture was concentrated invacuo. The residue was diluted with water (20 mL), and the resultingmixture was extracted with DCM (10 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo toafford the crude product as a brown solid (617 mg).

MS (ESI, pos. ion) m/z: 370.1 [M+H]⁺.

Step 4) 1-(7-aminoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of1-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-2-yl)-2-methyl-propan-2-ol(617.8 mg, 1.67 mmol) in DCM (5 mL) was added a solution of HCl in EtOAc(20 mL, 3M). The reaction mixture was stirred at room temperature for 1hour and concentrated in vacuo. The residue was diluted with water (15mL), and the resulting mixture was adjusted to pH=9 with NaOH aqueoussolution (1 M) then concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/50 to 1/10 to (asolution of NH₃ in MeOH (7M))/DCM (v/v)=1/10) to afford the titlecompound as a yellow solid (343.2 mg, yield 33% for step 3) to step 4)).

MS (ESI, pos. ion) m/z: 206.1 [M+H]⁺.

Step 5)6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(50.0 mg, 0.14 mmol) and1-(7-aminoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol (27.0 mg, 0.13mmol) in 1,4-dioxane (1 mL) were added Pd(OAc)₂ (3.6 mg, 0.02 mmol),BINAP (9.2 mg, 0.02 mmol) and Cs₂CO₃ (93.2 mg, 0.29 mmol). The mixturewas stirred at 100° C. under N₂ atmosphere overnight and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/50 to 1/10 to (a solution of NH₃ inMeOH (7M))/DCM (v/v)=1/10) to afford the crude product as a yellowsolid, and then the crude product was purified by preparative TLC(MeOH/DCM (v/v)=1/6) to afford the target product as a yellow solid (8.2mg, yield 11%).

MS (ESI, pos. ion) m/z: 519.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.2132 [M+H]⁺, calculated value forC₂₅H₂₈ClN₁₀O [M+H]⁺ is 519.2131;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.28 (s, 1H), 8.13 (d, J=7.3 Hz, 1H),7.91 (s, 1H), 7.54 (d, J=6.0 Hz, 1H), 7.42 (d, J=9.6 Hz, 1H), 7.34 (s,1H), 6.97 (d, J=9.6 Hz, 1H), 4.47-4.39 (m, 3H), 3.54 (t, J=12.5 Hz, 2H),2.29 (d, J=12.1 Hz, 2H), 1.98-1.93 (m, 1H), 1.59-1.50 (m, 3H), 1.25 (s,6H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 158.5, 157.2, 156.7, 152.6, 141.1,130.7, 129.9, 128.6, 126.9, 116.8, 110.9, 110.6, 110.5, 107.3, 95.1,69.6, 48.1, 43.4, 38.6, 31.3, 28.9.

Example 396-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) ethyl 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

To a solution of 1,2-diamino-4-bromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (24.78 g, 63.8 mmol) in pyridine (200mL) was added ethyl 2-chloro-2-oxoacetate (14.5 mL, 130 mmol) at 0° C.The reaction mixture was moved to room temperature and stirred for 30min, then heated to 100° C. and stirred overnight. The mixture wasconcentrated in vacuo, the residue was diluted with water (300 mL), andthe resulting mixture was extracted with EtOAc (200 mL×3). The combinedorganic layers were washed with water (200 mL×3), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel column chromatography (EtOAc/PE (v/v)=1/6 to 1/4) to affordthe title compound as a yellow solid (0.96 g, yield 6.0%).

MS (ESI, pos. ion) m/z: 270.0 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.51 (d, J=7.2 Hz, 1H), 8.03 (s, 1H),7.28 (d, J=1.7 Hz, 1H), 4.56 (q, J=7.1 Hz, 2H), 1.49 (t, J=7.1 Hz, 3H).

Step 2) 2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of ethyl7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (830.0 mg, 3.07mmol) in tetrahydrofuran (20 mL) were added methylmagnesium bromide (3.0M in diethyl ether, 5.1 mL, 15 mmol) dropwise under N₂ atmosphere at−78° C. The mixture was moved to 0° C. and stirred overnight thenquenched with water (5 mL), and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/5 to 1/1)to afford the title compound as a white solid (402.2 mg, yield 51%).

MS (ESI, pos. ion) m/z: 256.1 [M+H]⁺.

Step 3)2-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol (402.2 mg,1.57 mmol) and diphenylmethanimine (429.1 mg, 2.37 mmol) in 1,4-dioxane(15 mL) were added Pd₂(dba)₃ (143.4 mg, 0.16 mmol), BINAP (97.6 mg, 0.16mmol) and Cs₂CO₃ (1.02 g, 3.13 mmol). The mixture was stirred at 100° C.under N₂ atmosphere overnight and then concentrated in vacuo. Theresidue was diluted with water (40 mL), and the resulting mixture wasextracted with DCM (30 mL×3). The combined organic layers were washedwith water (40 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo to afford the title compound as brown oil (556.7mg).

MS (ESI, pos. ion) m/z: 357.2 [M+H]⁺.

Step 4) 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of2-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol(556.7 mg, 1.56 mmol) in DCM (5 mL) was added a solution of HCl in EtOAc(15 mL, 3 M). The reaction mixture was stirred at room temperature for 1hour and then concentrated in vacuo. The residue was diluted with water(15 mL), and the resulting mixture was adjusted to pH=9 with NaOHaqueous soultion (1M) and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/50 to1/20 to 1/10) to afford the title compound as a yellow solid (220.4 mg,yield 73% for steps 3) to step 4)).

MS (ESI, pos. ion) m/z: 193.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.23 (d, J=7.3 Hz, 1H), 6.70 (d, J=1.6Hz, 1H), 6.41 (dd, J=7.3, 2.1 Hz, 1H), 4.25 (s, 2H), 1.71 (s, 6H).

Step 5)6-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(140.3 mg, 0.40 mmol) and2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol (77.2 mg, 0.40mmol) in 1,4-dioxane (6 mL) were added Pd(OAc)₂ (9.5 mg, 0.04 mmol),BINAP (25.2 mg, 0.04 mmol) and Cs₂CO₃ (262.1 mg, 0.80 mmol). The mixturewas stirred at 100° C. under N₂ atmosphere overnight and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/50 to 1/30) to afford the crude productas a pink solid, the crude product was stirred with EtOH (6 mL) and thenfiltered. The filter cake was collected to afford the target product asa white solid (104.4 mg, yield 52%).

MS (ESI, pos. ion) m/z: 505.5 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 505.1974 [M+H]⁺, calculated value forC₂₄H₂₆ClN₁₀O [M+H]⁺ is 505.1974;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.88 (s, 1H), 8.68 (d, J=7.4 Hz, 1H),8.51 (d, J=2.0 Hz, 1H), 8.32 (d, J=1.6 Hz, 1H), 8.09 (s, 1H), 7.86 (dd,J=9.1, 2.2 Hz, 1H), 7.32 (dd, J=7.5, 2.1 Hz, 1H), 7.13 (d, J=7.8 Hz,1H), 7.02 (d, J=9.1 Hz, 1H), 5.08 (s, 1H), 4.55 (d, J=12.2 Hz, 2H),4.41-4.31 (m, 1H), 3.14 (t, J=12.4 Hz, 2H), 2.01 (d, J=10.3 Hz, 2H),1.68-1.61 (m, 2H), 1.53 (s, 6H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 172.2, 159.0, 157.5, 156.9, 153.2,152.7, 151.6, 142.0, 140.0, 128.1, 118.8, 107.9, 106.5, 105.2, 99.0,94.8, 68.1, 48.4, 43.8, 30.5, 29.7.

Example 406-(4-((5-chloro-2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 4-bromo-2-hydrazinylpyridine

To a suspension of 4-bromo-2-fluoropyridine (6.00 g, 34.1 mmol) in EtOH(60 mL) was added hydrazine hydrate (21 mL, 346 mmol, mass %=80%). Themixture was heated to 75° C. and stirred overnight and then cooled downto room temperature. To the mixture was added NaOH aqueous solution(25.0 mL, 4 M) and water (200 mL), the resulting mixture was stirred at0° C. for 15 min, and filtered. The filter cake was washed with water(100 mL), and then dried in vacuo to afford the title compound as ayellow solid (4.60 g, yield 71%).

MS (ESI, pos. ion) m/z: 188.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.92 (d, J=5.4 Hz, 1H), 6.98 (d, J=1.4Hz, 1H), 6.81 (dd, J=5.4, 1.6 Hz, 1H), 5.89 (s, 1H), 3.78 (s, 2H).

Step 2) ethyl 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate

To a suspension of 4-bromo-2-hydrazinylpyridine (4.60 g, 24.5 mmol) inMeOH (60 mL) was added ethyl 2-oxoacetate (5.99 g, 29.3 mmol). Themixture was heated to 60° C. and stirred for 2 h, then cooled down toroom temperature and concentrated in vacuo. The residue was dissolved inDCM (60 mL) and the resulting solution was cooled down to 0° C., and(diacetoxyiodo)benzene (10.26 g, 31.85 mmol) was added in portions.After addition, the mixture was moved to room temperature and stirredovernight. The mixture was diluted with DCM (200 mL), and then washedwith water (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/5) to afford the title compound as awhite solid (5.10 g, yield 77%).

MS (ESI, pos. ion) m/z: 270.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.03 (d, J=7.3 Hz, 1H), 8.14 (s, 1H),7.19 (dd, J=7.4, 1.7 Hz, 1H), 4.58 (q, J=7.1 Hz, 2H), 1.51 (t, J=7.1 Hz,3H).

Step 3) 2-(7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol

At 0° C., to a suspension of ethyl7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (5.00 g, 18.5 mmol)in THF (100 mL) was slowly added methylmagnesium bromide (18.5 mL, 56mmol, 3.0 M in THF). After addition, the mixture was stirred at 0° C.for 1 h, then to the mixture was slowly added saturated NH₄Cl aqueoussolution (50 mL), water (100 mL) and EtOAc (200 mL). The mixture wasfiltered through a pad of diatomaceous earth. The organic layer offiltrate was separated, and the aqueous layer was extracted with EtOAc(200 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=100/1 to 50/1 to 20/1)to afford the title compound as a white solid (3.0 g, yield 63%).

MS (ESI, pos. ion) m/z: 256.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.56 (d, J=7.4 Hz, 1H), 7.78 (s, 1H),6.87 (d, J=7.4 Hz, 1H), 1.79 (s, 6H).

Step 4)2-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol

To a suspension of2-(7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol (3.00 g, 11.7mmol) in 1,4-dioxane (50 mL) was added Pd₂(dba)₃ (1.08 g, 1.18 mmol),BINAP (1.46 g, 2.36 mmol), Cs₂CO₃ (7.65 g, 23.5 mmol) anddiphenylmethanimine (4.27 g, 23.56 mmol). The mixture was degassed andrefilled with N₂ for several times and heated to 105° C. and stirredovernight. The mixture was then concentrated in vacuo. The residue wasdiluted with water (50 mL) and DCM (50 mL), then filtered through a padof diatomaceous earth. The filtrate was extracted with DCM (50 mL). Theorganic layer of filtrate was separated, and the aqueous layer wasextracted with DCM (100 mL×3). The combined organic layers were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford a brown sticky liquid for 6.80 g,wherein the target product was just for 4.17 g (yield 100%). The crudeproduct was used for next step without further purification.

MS (ESI, pos. ion) m/z: 357.4 [M+H]⁺.

Step 5) 2-(7-amino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol

To a suspension of2-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol(4.17 g, 11.7 mmol) in DCM (100 mL) was added a solution of hydrogenchloride in EtOAc (100 mL, 300 mmol, 3.0 M). The mixture was stirred atroom temperature overnight and then concentrated in vacuo. The residuewas diluted with water (100 mL), and the resulting mixture was adjustedto pH=10 with saturated Na₂CO₃ aqueous solution, then extracted with DCM(200 mL×5). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=50/1 to 25/1 to 10/1) to afford the title compound as a yellowsolid (0.88 g, yield 39%).

MS (ESI, pos. ion) m/z: 193.1 [M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.49 (d, J=7.6 Hz, 1H), 6.52 (dd,J=7.6, 2.1 Hz, 1H), 6.44 (d, J=1.4 Hz, 1H), 1.72 (s, 6H).

Step 6)6-(4-((5-chloro-2-((3-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(0.12 g, 0.35 mmol) in 1,4-dioxane (15.0 mL) were added2-(7-amino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol (0.081 g, 0.42mmol), Pd(OAc)₂ (0.017 g, 0.077 mmol), BIANP (0.046 g, 0.074 mmol) andCs₂CO₃ (0.25 g, 0.75 mmol). The mixture was degassed and refilled withN₂ for several times and heated to 105° C. and stirred for 3 h. Themixture was then concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=100/1 to 50/1 to 30/1) to afford the title compound as a lightyellow solid (45 mg, yield 26%).

MS (ESI, pos. ion) m/z: 505.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 505.1985 [M+H]⁺, calculated value forC₂₄H₂₆ClN₁₀O [M+H]⁺ is 505.1974;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.81 (s, 1H), 8.55 (d, J=7.6 Hz, 1H),8.51 (d, J=1.9 Hz, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.86 (dd, J=9.1, 2.3Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.09-7.00 (m, 2H), 4.58 (d, J=13.1 Hz,2H), 4.42-4.30 (m, 1H), 3.15 (t, J=12.4 Hz, 2H), 2.08-2.00 (m, 2H),1.72-1.57 (m, 8H);

¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 159.44, 158.05, 157.33, 153.81,153.08, 151.75, 150.76, 140.47, 139.52, 125.84, 119.23, 109.66, 106.97,105.38, 96.82, 95.34, 68.77, 60.21, 49.18, 44.32, 31.02, 29.34, 21.22,14.55.

Example 416-(4-((5-chloro-2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

Step 1) tert-butyl4-((5-chloro-2-((3-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate

To a suspension of tert-butyl4-((2,5-dichloropyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(0.30 g, 0.80 mmol) in 1,4-dioxane (20 mL) were added2-(7-amino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol (0.19 g, 0.98mmol), Pd(OAc)₂ (0.038 g, 0.17 mmol), BINAP (0.10 g, 0.17 mmol) andCs₂CO₃ (0.54 g, 1.66 mmol). The mixture was degassed and refilled withN₂ for several times and heated to 105° C. and stirred for 3 h. Themixture was then concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=50/1 to 20/1) to affordthe title compound as a light yellow solid (0.36 g, yield 85%).

MS (ESI, pos. ion) m/z: 531.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.45 (d, J=7.5 Hz, 1H), 8.25 (s, 1H),7.94 (s, 1H), 6.70 (s, 1H), 5.16 (d, J=8.6 Hz, 1H), 4.44-4.17 (m, 1H),4.15-3.96 (m, 2H), 3.14-2.86 (m, 2H), 2.78-2.55 (m, 1H), 2.19-2.08 (m,1H), 1.85 (s, 3H), 1.82 (s, 3H), 1.74-1.64 (m, 1H), 1.47 (s, 9H),1.31-1.19 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Step 2)2-(7-((5-chloro-4-((3-ethylpiperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol

To a suspension of tert-butyl4-((5-chloro-2-((3-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidine-1-carboxylate(0.38 g, 0.72 mmol) in DCM (10 mL) was added a solution of hydrogenchloride in EtOAc (10.0 mL, 30 mmol, 3.0 M). The mixture was stirred atroom temperature overnight and then concentrated in vacuo. The residuewas diluted with water (10 mL), and the resulting mixture was adjustedto pH=9 with saturated Na₂CO₃ aqueous solution, then extracted with DCM(50 mL×4). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (DCM/(a solution of NH₃ in MeOH (3M))(v/v)=50/1 to 25/1 to 10/1) to afford the title compound as a yellowsolid (0.18 g, yield 58%).

MS (ESI, pos. ion) m/z: 431.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.44 (d, J=7.5 Hz, 1H), 8.35 (s, 1H),8.15 (s, 1H), 7.83 (s, 1H), 6.66 (d, J=5.9 Hz, 1H), 5.21 (d, J=8.5 Hz,1H), 3.99-3.84 (m, 1H), 3.25-3.15 (m, 1H), 3.05 (d, J=12.2 Hz, 1H), 2.84(t, J=11.7 Hz, 1H), 2.46 (t, J=11.4 Hz, 1H), 2.15 (d, J=11.1 Hz, 1H),1.81 (s, 3H), 1.78 (s, 3H), 1.69-1.56 (m, 2H), 1.50-1.36 (m, 2H), 0.89(t, J=7.3 Hz, 3H).

Step 3)6-(4-((5-chloro-2-((3-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-ethylpiperidin-1-yl)nicotinonitrile

To a suspension of2-(7-((5-chloro-4-((3-ethylpiperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propan-2-ol(70 mg, 0.16 mmol) in EtOH (10 mL) were added 6-chloronicotinonitrile(46 mg, 0.33 mmol) and TEA (46 mg, 0.45 mmol). The mixture was heated toreflux and stirred overnight and the mixture was concentrated in vacuo.The residue was purified by silica gel column chromatography (DCM/(asolution of NH₃ in MeOH (3M)) (v/v)=100/1 to 50/1 to 30/1) to afford thetitle compound as a light yellow solid (50 mg, yield 58%).

MS (ESI, pos. ion) m/z: 533.5 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 533.2293 [M+H]⁺, calculated value forC₂₆H₃₀ClN₁₀O [M+H]⁺ is 533.2287;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.81 (s, 1H), 8.54 (d, J=7.7 Hz, 1H),8.52 (d, J=1.8 Hz, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.86 (dd, J=9.1, 2.1Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.10-6.96 (m, 2H), 4.66 (d, J=11.8 Hz,1H), 4.55 (d, J=12.6 Hz, 1H), 4.29-4.15 (m, 1H), 3.13 (t, J=12.5 Hz,1H), 2.78-2.65 (m, 1H), 2.06-1.94 (m, 1H), 1.84-1.71 (m, 1H), 1.64 (s,6H), 1.61-1.51 (m, 2H), 1.22-1.13 (m, 1H), 0.93-0.88 (m, 3H);

¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 158.85, 157.57, 157.37, 153.25,152.70, 151.29, 150.30, 140.07, 139.09, 125.40, 118.82, 109.19, 106.45,104.94, 96.31, 94.85, 68.30, 52.65, 48.14, 44.13, 40.97, 30.87, 28.87,22.37, 10.93.

Example 426-(4-((5-chloro-2-((3-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) ethyl 4-oxobutanoate

To a suspension of ethyl 4-hydroxybutanoate (5 g, 37.833 mmol) in DCM(100 mL) was added pyridinium chlorochromate (16.31 g, 75.66 mmol). Thereaction mixture was stirred at rt overnight and concentrated in vacuo.The residue was purified by flash silica gel column chromatography(PE/EtOAc (v/v)=10/1) to give the title product as colourless oil (2.68g, yield 54.4%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.77 (s, 1H), 4.13-4.08 (m, 2H), 2.75(t, J=6.6 Hz, 2H), 2.58 (t, J=6.6 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H).

Step 2) ethyl 3-bromo-4-oxobutanoate

To a suspension of ethyl 4-oxobutanoate (2.6 g, 20 mmol) in DCM (50 mL)was added molecular bromine (3.2 g, 20 mmol) dropwise at 0° C. Then thereaction mixture was stirred at rt for 1 hour and water (50 mL) wasadded then extracted with DCM (50 mL×3). The combined organic layerswere washed with brine (100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by flash silica gelcolumn chromatography (PE/EtOAc (v/v)=10/1) to give the title product asbrown oil (2.7 g, yield 65%).

¹H NMR (600 MHz, CDCl₃) δ (ppm): 9.52 (s, 1H), 4.66 (t, J=6.9 Hz, 1H),4.18 (q, J=7.1 Hz, 2H), 3.21 (dd, J=17.1, 7.2 Hz, 1H), 2.92 (dd, J=17.1,6.7 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H).

Step 3) ethyl 2-(7-bromoimidazo[1,2-a]pyridin-3-yl)acetate

To a solution of ethyl 3-bromo-4-oxobutanoate (2.7 g, 13 mmol) inethanol (20 mL) were added 4-bromopyridin-2-amine (2.2 g, 13 mmol). Themixture was stirred at 60° C. for 3 hours and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=500/1 to 100/1) to give the title compound as a yellow solid (1.3g, yield 36%).

MS(ESI, pos.ion)m/z: 283.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94 (d, J=7.3 Hz, 1H), 7.81 (s, 1H),7.52 (s, 1H), 6.95 (d, J=7.2 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.90 (s,2H), 1.25 (t, J=7.1 Hz, 3H).

Step 4) 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)-2-methylpropan-2-ol

To a solution of ethyl 2-(7-bromoimidazo[1,2-a]pyridin-3-yl)acetate (2g, 7.0641 mmol) in anhydrous tetrahydrofuran (100 mL) was addedmethylmagnesium bromide (11.8 mL, 35.4 mmol, 3M in THF) dropwise at 0°C. Then the mixture was allow to moved to 0° C. and stirred overnight.The reaction mixture was quenched with saturated NH₄Cl aqueous solution(20 mL), then the reaction mixture was diluted with water (40 mL) andextracted with EtOAc (60 mL×3). The combined organic layers were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash silica gelcolumn chromatography (DCM/MeOH (v/v)=100/1 to 50/1) to give the titlecompound as a yellow solid (250 mg, yield 13.15%).

MS (ESI, pos. ion) m/z: 269.3 [M+H]⁺.

Step 5)1-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-3-yl)-2-methyl-propan-2-ol

To a solution of1-(7-bromoimidazo[1,2-a]pyridin-3-yl)-2-methylpropan-2-ol (150 mg,0.55733 mmol), diphenylmethanimine (152 mg, 0.8389 mmol) and t-BuONa(107 mg, 1.113 mmol) in 1,4-dioxane (20 mL) were added BINAP (35 mg,0.05621 mmol) and Pd₂(dba)₃ (26.3 mg, 0.0279 mmol). The mixture wasdegassed for 5 min and refilled with N₂ and then stirred at 100° C.overnight. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=5/1 to 1/1) to give the title compound as a yellow solid(100 mg, yield 48.56%).

MS (ESI, pos. ion) m/z: 370.1 [M+H]⁺.

Step 6) 1-(7-aminoimidazo[1,2-a]pyridin-3-yl)-2-methylpropan-2-ol

To a solution of1-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-3-yl)-2-methylpropan-2-ol(100 mg, 0.2706 mmol) in DCM (10 mL) was added a solution of hydrogenchloride in EtOAc (2 mL, 4 M). The reaction mixture was stirred at rtfor 2 hours and concentrated in vacuo. The residue was dissolved inwater (5 mL) and adjusted to pH=8-9 with a saturated NaHCO₃ aqueoussolution, then the mixture was concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/(a solution of NH₃ inMeOH (7M)) (v/v)=20/1) to give the title compound as a yellow solid (45mg, yield 81.01%).

MS (ESI, pos. ion) m/z: 206.2 [M+H]⁺.

Step 7)6-(4-((5-chloro-2-((3-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(32 mg, 0.09164 mmol),1-(7-aminoimidazo[1,2-a]pyridin-3-yl)-2-methylpropan-2-ol (23 mg,0.11205 mmol) and Cs₂CO₃ (90 mg, 0.27623 mmol) in 1,4-dioxane (10 mL)were added Pd(OAc)₂ (2 mg, 0.00891 mmol) and BINAP (6 mg, 0.00966 mmol).The mixture was degassed for 2 min and refilled with N₂ and then stirredat 100° C. for 4 h. The mixture was concentrated in vacuo and theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1 to 20/1) to give the title compound as a light yellow solid(3.3 mg, yield 7.0%).

MS (ESI, pos. ion) m/z: 518.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 518.2186 [M+H]⁺, calculated value forC₂₆H₂₉ClN₉O [M+H]⁺ is 518.2178;

¹H NMR (600 MHz, CD₃OD) δ (ppm): 8.43 (s, 2H), 8.26 (s, 1H), 8.01 (s,1H), 7.66 (d, J=8.2 Hz, 1H), 7.61-7.51 (m, 2H), 7.40 (s, 2H), 6.75 (d,J=8.4 Hz, 1H), 5.38 (t, J=4.7 Hz, 1H), 4.48 (s, 1H), 4.41 (s, 2H), 3.42(s, 2H), 3.05 (s, 2H), 2.05 (dd, J=12.4, 6.5 Hz, 2H), 1.60 (d, J=9.8 Hz,2H), 1.29 (s, 6H);

¹³C NMR (150 MHz, CD₃OD) δ (ppm): 159.2, 157.3, 157.1, 152.8, 152.7,139.9, 131.1, 129.9, 129.7, 128.9, 128.6, 128.4, 126.1, 118.7, 109.7,106.1, 95.8, 43.5, 37.0, 35.8, 31.9, 31.4, 29.7.

Example 436-(4-((5-chloro-2-((3-(1-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 7-bromoimidazo[1,2-a]pyridine-3-carbaldehyde

To a suspension of 4-bromopyridin-2-amine (10.00 g, 57.80 mmol) in EtOH(120 mL) was added 2-bromomalonaldehyde (13.13 g, 86.98 mmol) and4-methylbenzenesulfonic acid hydrate (2.25 g, 11.8 mmol). The mixturewas placed in a sealed tube and heated to 100° C. and stirred overnight.The mixture was then concentrated in vacuo. The residue was diluted withDCM (100 mL) and water (100 mL), and then adjusted to pH=10 with 15%NaOH aqueous solution. The mixture was allowed to stand stratification,and the separated aqueous layer was extracted with DCM (100 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/10 to 1/5 to 1/3) to give the titlecompound as a brown solid (12.1 g, yield 93%).

MS (ESI, pos. ion) m/z: 225.0 [M+H]⁺.

Step 2) 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)ethanol

At 0° C., to a suspension of7-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (12.1 g, 53.8 mmol) inanhydrous THF (130 mL) was slowly added methylmagnesium bromide (27.0mL, 81 mmol, 3.0 M in THF). The mixture was stirred at 0° C. for 1 h,and then quenched with saturated NH₄Cl aqueous solution (50 mL) andwater (50 mL). The mixture was allowed to stand stratification, and theseparated aqueous layer was extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE (v/v)=1/2 to 1/1to 2/1) to afford the title compound as a yellow solid (3.00 g, yield23%).

MS (ESI, pos. ion) m/z: 241.0 [M+H]⁺.

Step 3) 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)ethanone

At 0° C., to a suspension of1-(7-bromoimidazo[1,2-a]pyridin-3-yl)ethanol (3.00 g, 12.4 mmol) in DCM(100 mL) was added Dess-Martin periodinane (7.95 g, 18.7 mmol) and themixture was stirred at room temperature overnight. The resulting mixturewas diluted with saturated Na₂CO₃ aqueous solution (100 mL), and theresulting mixture was allowed to stand stratification. The separatedaqueous layer was extracted with DCM (100 mL×3), and the combinedorganic layers was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/5 to 1/2) to afford the title compoundas a yellow solid (1.30 g, yield 44%).

MS (ESI, pos. ion) m/z: 239.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.51 (d, J=7.3 Hz, 1H), 8.30 (s, 1H),7.95 (d, J=1.2 Hz, 1H), 7.19 (dd, J=7.3, 1.7 Hz, 1H), 2.60 (s, 3H).

Step 4)1-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-3-yl)ethanone

To a suspension of 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)ethanone (1.30g, 5.44 mmol) in anhydrous 1,4-dioxane (40 mL) were added Pd₂(dba)₃(0.50 g, 0.55 mmol), BINAP (0.68 g, 1.10 mmol), Cs₂CO₃ (3.55 g, 10.89mmol) and diphenylmethanimine (1.98 g, 10.92 mmol). The mixture wasdegassed and refilled with N₂ for several times and heated to 105° C.and stirred overnight. The mixture was then concentrated in vacuo. Theresidue was diluted with water (100 mL), and the resulting mixture wasextracted with DCM (100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford theresidue as red sticky liquid (3.80 g), wherein the target product wasjust 1.85 g (yield 100%).

MS (ESI, pos. ion) m/z: 340.1 [M+H]⁺.

Step 5) 1-(7-aminoimidazo[1,2-a]pyridin-3-yl)ethanone

To a suspension of1-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-3-yl)ethanone (1.85g, 5.45 mmol) in DCM (50 mL) was added a solution of hydrogen chloridein EtOAc (50 mL, 150 mmol, 3 M). The mixture was stirred at roomtemperature overnight and then concentrated in vacuo. The residue wasdiluted with DCM (100 mL) and water (50 mL), and the resulting mixturewas adjusted to pH=10 with 10% NaOH aqueous solution. The mixture wasallowed to stand stratification and the separated aqueous layer wasextracted with DCM (200 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica gel column chromatography (DCM/(a solution of NH₃in MeOH (3M)) (v/v)=100/1 to 50/1 to 25/1) to afford the title compoundas a yellow solid (0.25 g, yield 26%).

MS (ESI, pos. ion) m/z: 176.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.37 (d, J=7.4 Hz, 1H), 8.15 (s, 1H),6.76 (d, J=1.9 Hz, 1H), 6.49 (dd, J=7.4, 2.1 Hz, 1H), 4.26 (s, 2H), 2.52(s, 3H).

Step 6)6-(4-((2-((3-acetylimidazo[1,2-a]pyridin-7-yl)amino)-5-chloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(0.20 g, 0.57 mmol) in anhydrous 1,4-dioxane (10 mL) were added1-(7-aminoimidazo[1,2-a]pyridin-3-ypethanone (0.10 g, 0.57 mmol),Pd(OAc)₂ (0.028 g, 0.12 mmol), BINAP (0.073 g, 0.12 mmol) and Cs₂CO₃(0.37 g, 1.14 mmol). The mixture was degassed and refilled with N₂ forseveral times and heated to 105° C. and stirred overnight. The mixturewas then concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=100/1 to 50/1 to 25/1) to affordthe title compound as a light yellow solid (0.23 g, yield 83%).

MS (ESI, pos. ion) m/z: 488.1 [M+H]⁺.

Step 7)6-(4-((5-chloro-2-((3-(1-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2-((3-acetylimidazo[1,2-a]pyridin-7-yl)amino)-5-chloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(0.23 g, 0.47 mmol) in MeOH (5 mL) and DCM (5 mL) was added sodiumborohydride (0.11 g, 2.86 mmol). The mixture was stirred at roomtemperature overnight and then concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to50/1 to 20/1) to get the crude product. The crude product was stirredwith MeOH (2.0 mL) for 30 min, filtered and the filter cake was dried invacuo to afford the title compound as a grey white solid (25 mg, yield11%).

MS (ESI, pos. ion) m/z: 490.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 490.1868 [M+H]⁺, calculated value forC₂₄H₂₅ClN₉O [M+H]⁺ is 490.1865;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.58 (s, 1H), 8.51 (d, J=2.1 Hz, 1H),8.28 (d, J=7.5 Hz, 1H), 8.23 (d, J=1.3 Hz. 1H), 8.04 (s, 1H), 7.85 (dd,J=9.1, 2.2 Hz, 1H), 7.27 (s, 1H), 7.10 (dd, J=7.5, 1.7 Hz, 1H), 7.07 (d,J=7.8 Hz, 1H), 7.02 (d, J=9.1 Hz, 1H), 5.24 (d, J=6.0 Hz, 1H), 5.06-5.02(m, 1H), 4.59-4.53 (m, 2H), 4.40-4.35 (m, 1H), 3.19-3.15 (m, 2H),2.04-2.00 (m, 2H), 1.66-1.60 (m, 2H), 1.56 (d, J=6.5 Hz, 3H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 159.38, 158.17, 157.27, 153.83,153.12, 146.66, 140.47, 137.82, 130.13, 129.79, 127.50, 125.47, 119.30,107.62, 106.96, 101.13, 95.20, 59.86, 49.06, 44.28, 31.03, 22.02.

Example 446-(4-((5-chloro-2-((2-(1-hydroxycyclopropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1)N-(1-amino-4-bromopyridin-2(1H)-ylidene)-1-hydroxycyclopropanecarboxamide

To a solution of 1-hydroxycyclopropanecarboxylic acid (1.03 g, 10.09mmol) in THF (20 mL) were added DMF (1 mL) and sulfurous dichloride (3mL, 41.35 mmol) at 0° C. The reaction mixture was stirred at rt for 3hours and 1,2-diamino-4-bromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (1.96 g, 5.05 mmol) was added. Thereaction mixture was stirred at rt overnight and filtered to give thetitle compound as a yellow green solid (1.38 g, yield 100%).

MS (ESI, pos. ion) m/z: 272.1 [M+H]⁺.

Step 2) 1-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanol

To a suspension ofN-(1-amino-4-bromopyridin-2(1H)-ylidene)-1-hydroxycyclopropanecarboxamide(1.57 g, 5.77 mmol), DMAP (706.3 mg, 5.78 mmol) and DIPEA (395.2 mg,3.06 mmol) in MeCN (10 mL) was added Benzenesulfonamide (5.6 mL, 22.90mmol). The reaction mixture was stirred at rt for 1 hour and then heatedto reflux and stirred overnight and then concentrated in vacuo. Theresidue was purified by flash silica gel column chromatography (EtOAc/PE(v/v)=1/1) to give the title compound as a white solid (470.2 mg, yield32.1%).

MS (ESI, pos. ion) m/z: 254.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.35 (d, J=7.2 Hz, 1H), 7.82 (d, J=1.4Hz, 1H), 7.08 (dd, J=7.2, 1.8 Hz, 1H), 3.94 (s, 1H), 1.39 (s, 4H).

Step 3)1-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanol

To a solution of1-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanol (424.5 mg,1.67 mmol) and diphenylmethanimine (475.8 mg, 2.63 mmol) in 1,4-dioxane(30 mL) were added Pd₂(dba)₃ (80.8 mg, 0.09 mmol), BINAP (98%, 109.5 mg,0.17 mmol) and Cs₂CO₃ (1.12 g, 3.37 mmol). The reaction mixture wasstirred at 100° C. for 3 h, cooled down to rt and concentrated in vacuo.The residue was purified by flash silica gel column chromatography(EtOAc/PE (v/v)=7/3) to give the title compound as a yellow solid (142.8mg, yield 24.1%).

MS (ESI, pos. ion) m/z: 355.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.22 (d, J=7.2 Hz, 1H), 7.76 (d, J=7.6Hz, 2H), 7.56-7.49 (m, 1H), 7.48-7.39 (m, 3H), 7.30 (d, J=7.1 Hz, 2H),7.14 (d, J=6.1 Hz, 2H), 6.82 (d, J=1.3 Hz, 1H), 6.44 (dd, J=7.2, 2.0 Hz,1H), 3.44 (s, 1H), 1.34-1.32 (m, 4H).

Step 4) 1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanol

To a solution of1-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanol(127.0 mg, 0.36 mmol) in THF (10 mL) was added a solution of HCl inwater (4 mL, 16 mmol, 4 M) dropwise. The reaction mixture was stirred atrt for 1 hour and adjusted to pH=10 with a Na₂CO₃ powder, then extractedwith DCM (100 mL×3). The combined organic phases were concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/10) to give the title compound as a yellow solid (63.5mg, yield 93.2%).

MS (ESI, pos. ion) m/z: 191.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.19 (d, J=7.2 Hz, 1H), 6.63 (d, J=1.7Hz, 1H), 6.35 (dd, J=7.3, 2.1 Hz, 1H), 4.18 (s, 2H), 3.39 (s, 1H),1.38-1.32 (m, 4H).

Step 5)6-(4-((5-chloro-2-((2-(1-hydroxycyclopropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(62.0 mg, 0.18 mmol) and1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanol (49.9 mg,0.26 mmol) in 1,4-dioxane (10 mL) were added Pd(OAc)₂ (10.2 mg, 0.045mmol), BINAP (98%, 24.9 mg, 0.039 mmol) and Cs₂CO₃ (98%, 128.3 mg, 0.38mmol). The reaction mixture was stirred at 100° C. for 3 hours andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/10) to give the title compound as abeige solid (24.2 g, yield 27.1%).

MS (ESI, pos. ion) m/z: 503.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.07 (s, 1H), 8.85 (d, J=7.5 Hz,1H), 8.51 (s, 2H), 8.12 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.4Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 6.65 (s, 1H),4.57 (d, J=12.8 Hz, 2H), 4.43-4.29 (m, 1H), 3.20-3.06 (m, 2H), 1.74-1.60(m, 2H), 1.51-1.40 (m, 2H), 1.10 (t, J=7.2 Hz, 2H), 0.85 (t, J=6.3 Hz,2H).

Example 45 methyl2-(7-((5-chloro-4-((1-(5-cyanopyridin-2-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate

Step 1) ethyl 2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate

To a solution of 1,2-diamino-4-bromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (4.20 g, 10.8 mmol) and diethyl3-oxopentanedioate (4.0 mL, 22.0 mmol) in EtOH (60 mL) was added NaOH(436.4 mg, 10.9 mmol). The reaction mixture was stirred at rt for 5 hand concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (EtOAc/PE (v/v)=1/4) to give the title compound asa yellow solid (2.25 g, 73%).

MS (ESI, pos. ion) m/z: 284.0 [M+H]⁺.

Step 2) methyl 2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate

To a solution of ethyl2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate (1.75 g, 6.16mmol) in THF (45 mL) was added methylmagnesium bromide (3.0 M in diethylether, 10.3 mL, 30.9 mmol) dropwise at −78° C. under N₂ atmosphere.After addition, the reaction mixture was warmed up to 0° C., stirredovernight and quenched with water (3 mL), then concentrated in vacuo.The residue was purified by a silica gel column chromatography (EtOAc/PE(v/v)=1/1) to give the title compound as a white solid (220.0 mg, 13%).

MS (ESI, pos. ion) m/z: 270.1 [M+H]⁺.

Step 3) methyl2-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate

To a solution of methyl2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate (220.0 mg, 0.81mmol) and diphenylmethanimine (196.2 mg, 1.08 mmol) in 1,4-dioxane (7mL) were added Pd₂(dba)₃ (76.2 mg, 0.083 mmol), BINAP (54.6 mg, 0.088mmol) and Cs₂CO₃ (532.1 mg, 1.63 mmol). The reaction mixture was stirredat 100° C. for 6 h under N₂ atmosphere, then concentrated in vacuo. Theresidue was added water (20 mL), the resulted mixture was extracted withDCM (15 mL×2). The combined organic phases were washed with water (15mL×2), dried over Na₂SO₄ and concentrated in vacuo to give the titlecompound as brown oil, which was used to the next step without furtherpurification.

MS (ESI, pos. ion) m/z: 371.2 [M+H]⁺.

Step 4) methyl 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate

To a solution of methyl2-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate(301.7 mg, 0.81 mmol) in THF (4 mL) was added a solution of HCl in water(4M, 4 mL, 16 mmol). The reaction mixture was stirred at rt for 2 h andconcentrated in vacuo. The residue was added water (3 mL), adjusted topH=9 with a saturated Na₂CO₃ aqueous solution and concentrated in vacuo.The residue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/10) to give the title compound as a yellow solid (42.2 mg, 25%for 2 steps).

MS (ESI, pos. ion) m/z: 207.2 [M+H]⁺.

Step 5) methyl2-(7-((5-chloro-4-((1-(5-cyanopyridin-2-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(55.3 mg, 0.16 mmol) and methyl2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate (42.2 mg, 0.20mmol) in 1,4-dioxane (3 mL) were added Pd(OAc)₂ (4.6 mg, 0.020 mmol),BINAP (12.4 mg, 0.020 mmol) and Cs₂CO₃ (108.3 mg, 0.33 mmol). Thereaction mixture was stirred at 100° C. overnight under N₂ atmosphereand concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (MeOH/DCM (v/v)=1/20) to give the title compoundas a gray solid (45.1 mg, 18%).

MS (ESI, pos. ion) m/z: 519.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.1793; calculated value for C₂₄H₂₄ClN₁₀O₂[M+H]⁺ is 519.1772;

¹H NMR (600 MHz, CDCl₃): δ (ppm) 8.41 (d, J=1.9 Hz, 1H), 8.34 (d, J=7.4Hz, 1H), 8.25 (d, J=1.7 Hz, 1H), 7.98 (s, 1H), 7.62 (dd, J=9.0, 2.3 Hz,1H), 7.43 (s, 1H), 7.02 (dd, J=7.1, 1.2 Hz, 1H), 6.66 (d, J=9.0 Hz, 1H),5.27 (d, J=7.3 Hz, 1H), 4.43 (d, J=13.6 Hz, 2H), 4.35-4.28 (m, 1H), 3.94(s, 2H), 3.74 (s, 3H), 3.33-3.27 (m, 2H), 2.25 (dd, J=13.5, 3.6 Hz, 2H),1.61-1.54 (m, 2H);

¹³C NMR (100 MHz, CDCl₃): δ (ppm) 169.9, 161.1, 159.3, 157.4, 157.3,153.2, 152.9, 152.7, 141.5, 140.1, 127.8, 118.7, 108.2, 106.8, 106.0,100.8, 96.6, 52.5, 48.8, 43.7, 35.2, 31.6.

Example 466-(4-((5-chloro-2-((1-methyl-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) N-(diphenylmethylene)-1-methyl-1H-benzo[d]imidazol-5-amine

A mixture of 5-bromo-1-methyl-1H-benzo[a]imidazole (302.3 mg, 1.432mmol), diphenylmethanimine (341.5 mg, 1.885 mmol), t-BuONa (271.1 mg,2.821 mmol), BINAP (89.7 mg, 0.144 mmol) and Pd₂(dba)₃ (130.6 mg, 0.1426mmol) in 1,4-dioxane (10 mL) was heated to 100° C. and stirred overnightunder N₂ atmosphere and then concentrated in vacuo. The residue wasdiluted with water (40 mL) and the resulting mixture was extracted witha mixed solvent of DCM/MeOH (10/1 (v/v), 50 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the crude product as a brown solid (0.446 g), which wasused directly in the next step without further purification.

MS (ESI, pos.ion) m/z: 312.4 [M+H]⁺.

Step 2) 1-methyl-1H-benzo[d]imidazol-5-amine

A mixture of N-(diphenylmethylene)-1-methyl-1H-benzo[d]imidazol-5-amine(0.446 g, 1.43 mmol) in a solution of hydrogen chloride in EtOAc (8 mL,32 mmol, 4 M) was stirred at rt for 7 h. The reaction solution waswashed with water (30 mL×2), the combined aqueous phases were adjustedto pH=12 with NaOH powder, the resulting mixture was extracted with amixed solvent of DCM/MeOH (10/1 (v/v), 100 mL×4). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/(a solution of NH₃ in MeOH (7M)) (v/v)=60/1) to give the titlecompound as a light yellow solid (100 mg, yield 47.4%).

MS (ESI, pos.ion) m/z: 148.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.72 (s, 1H), 7.16 (d, J=8.5 Hz, 1H),7.08 (d, J=1.9 Hz, 1H), 6.75 (dd, J=8.5, 1.9 Hz, 1H), 3.77 (s, 3H).

Step 3)6-(4-((5-chloro-2-((1-methyl-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

A mixture of 1-methyl-1H-benzo[d]imidazol-5-amine (100 mg, 0.67944mmol),6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(182 mg, 0.5212 mmol), Cs₂CO₃ (508.7 mg, 1.561 mmol), BINAP (34.6 mg,0.0556 mmol) and Pd(OAc)₂ (12.8 mg, 0.0570 mmol) was dissolved with1,4-dioxane (10 mL). The reaction solution was heated to 100° C. andstirred for 4 hours under N₂ atmosphere and then concentrated in vacuo.The residue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1) to give the title compound as a white solid (54.4 mg, yield22.7%).

MS (ESI, pos.ion) m/z: 460.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.20 (s, 1H), 8.49 (d, J=2.0 Hz, 1H),8.22 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.84 (dd, J=9.1, 2.3 Hz, 1H),7.48 (dd, J=8.7, 1.5 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.99 (d, J=9.1 Hz,1H), 6.88 (d, J=7.8 Hz, 1H), 4.54 (d, J=12.1 Hz, 2H), 4.37-4.29 (m, 1H),3.79 (s, 3H), 3.10 (t, J=12.5 Hz, 2H), 2.00 (d, J=10.6 Hz, 2H), 1.60(qd, J=12.5, 3.8 Hz, 2H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 159.0, 158.3, 156.9, 153.6, 152.8,144.7, 143.7, 140.1, 135.6, 130.1, 119.0, 115.9, 109.6, 109.2, 106.6,102.9, 94.8, 44.0, 30.8, 30.7.

Example 476-(4-((5-chloro-2-((l-methyl-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) N-(diphenylmethylene)-1-methyl-1H-benzo[d][1,2,3]triazol-5-amine

A mixture of 5-bromo-1-methyl-1H-benzo[d][1,2,3]-triazole (302.3 mg,1.426 mmol), diphenylmethanimine (342.5 mg, 1.890 mmol), t-BuONa (274.2mg, 2.853 mmol), BINAP (87.8 mg, 0.141 mmol) and Pd₂(dba)₃ (131.4 mg,0.1435 mmol) in 1,4-dioxane (10 mL) was heated to 100° C. and stirredfor 6 hours under N₂ atmosphere and concentrated in vacuo. The residuewas diluted with water (50 mL) and the resulting mixture was extractedwith a mixed solvent of DCM/MeOH (10/1 (v/v), 80 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated invacuo to give the title compound as a brown solid (445.4 mg), which wasused directly in the next step without further purification.

MS (ESI, pos.ion) m/z: 313.2 [M+H]⁺.

Step 2) 1-methyl-1H-benzo[d][1,2,3]triazol-5-amine

N-(diphenylmethylene)-1-methyl-1H-benzo[d][1,2,3]triazol-5-amine (445.4mg, 1.426 mmol) was dissolved in a solution of hydrogen chloride inEtOAc (10 mL, 40 mmol, 4 M). The reaction mixture was stirred at rtovernight and then washed with water (20 mL×3). The combined aqueousphase was adjusted to pH=12 with NaOH powder. The resulting mixture wasextracted with a mixed solvent of DCM/MeOH (10/1 (v/v), 100 mL×4), thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/(a solution of NH₃ in MeOH (7M)) (v/v)=100/1) togive the title compound as a light yellow solid (151 mg, yield 71.5%).

MS (ESI, pos.ion) m/z: 149.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.30 (d, J=8.7 Hz, 1H), 7.18 (d, J=1.8Hz, 1H), 6.94 (dd, J=8.7, 1.9 Hz, 1H), 4.21 (s, 3H), 3.82 (s, 2H).

Step 3)6-(4-((5-chloro-2-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

A mixture of 1-methyl-1H-benzo[d][1,2,3]triazol-5-amine (64.8 mg, 0.437mmol),6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(147.6 mg, 0.4215 mmol), Cs₂CO₃ (301.4 mg, 0.9251 mmol), BINAP (27.5 mg,0.0442 mmol) and Pd(OAc)₂ (10.2 mg, 0.0454 mmol) was dissolved in1,4-dioxane (10 mL). The reaction mixture was heated to 100° C. andstirred overnight under N₂ atmosphere and then concentrated in vacuo.The residue was purified by silica gel column chromatography (DCM/MeOH(v/v)=60/1) to give the title compound as a white solid (68.1 mg, yield48.6%).

MS (ESI, pos.ion) m/z: 462.4 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 462.1671 [M+H]⁺, calculated value forC₂₁F₂₁ClN₁₁ [M+H]⁺ is 462.1670;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.51 (s, 1H), 8.61 (s, 1H), 8.01 (s,1H), 7.87 (d, J=9.7 Hz, 1H), 7.72 (s, 2H), 7.44 (d, J=9.7 Hz, 1H), 6.99(d, J=7.8 Hz, 1H), 4.66 (d, J=13.2 Hz, 2H), 4.45-4.34 (m, 1H), 4.25 (s,3H), 3.23 (t, J=12.4 Hz, 2H), 2.08 (d, J=11.0 Hz, 2H), 1.69 (qd, J=12.3,3.5 Hz, 2H);

¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 158.7, 158.1, 156.9, 153.5, 146.0,137.4, 131.1, 129.3, 128.4, 121.7, 117.5, 111.2, 110.1, 105.5, 103.7,44.0, 34.2, 30.6.

Example 486-(4-((5-chloro-2-((1,2-dimethyl-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 4-bromo-N-methyl-2-nitroaniline

To a solution of 4-bromo-1-fluoro-2-nitro-benzene (1.1 g, 5.0 mmol) andK₂CO₃ (1.28 g, 9.26 mmol) in DCM (20 mL) was added a solution ofmethylamine in water (3.5 mL, mass %=40%). The reaction mixture wasstirred at rt for 1.5 hours and then diluted with water (50 mL) and theresulting mixture was extracted with DCM (80 mL×3), the combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the title compound as a red solid (1.11 g, yield 96%).

MS (ESI, pos.ion) m/z: 231.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.31 (d, J=2.3 Hz, 1H), 8.01 (s, 1H),7.52 (dd, J=9.1, 2.2 Hz, 1H), 6.75 (d, J=9.1 Hz, 1H), 3.02 (d, J=5.1 Hz,3H).

Step 2) 4-bromo-M-methylbenzene-1,2-diamine

To the solution of 4-bromo-N-methyl-2-nitroaniline (1.11 g, 4.80 mmol)in EtOH (30 mL) were added zinc powder (3.6 g, 55 mmol) and saturatedNH₄Cl aqueous solution (4 mL), the mixture was heated to 60° C. for 1.5h. The precipitate in the reaction mixture was filtered out and thefilter cake was washed with MeOH (150 mL), and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=7/1 to 4/1) to give the title compound asbrown liquid (720 mg, yield 74.5%).

MS (ESI, pos.ion) m/z: 201.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.93 (dd, J=8.4, 2.2 Hz, 1H), 6.83 (d,J=2.2 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 3.34 (s, 3H), 2.83 (s, 3H).

Step 3) 5-bromo-1,2-dimethyl-1H-benzo[d]imidazole

To a solution of 4-bromo-N¹-methylbenzene-1,2-diamine (550 mg, 2.7355mmol) in pyridine (4 mL) was added dropwise acetyl chloride (337.6 mg,4.301 mmol) at 0° C., then the reaction mixture was heated to reflux andstirred overnight. The reaction solution was concentrated in vacuo, andthe residue was diluted with water (50 mL) and the resulting mixture wasextracted with a mixed solvent of DCM/MeOH (10/1 (v/v), 80 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH(v/v)=125/1 to 100/1) to give the title compoundas a light yellow solid (450 mg, yield 73.1%).

MS (ESI, pos.ion) m/z: 225.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.79 (s, 1H), 7.32 (dd, J=8.5, 1.5 Hz,1H), 7.12 (d, J=8.5 Hz, 1H), 3.69 (s, 3H), 2.58 (s, 3H).

Step 4) N-(diphenylmethylene)-1,2-dimethyl-1H-benzo[d]imidazol-5-amine

A mixture of 5-bromo-1,2-dimethyl-1H-benzo[d]imidazole (450 mg, 1.9993mmol), diphenylmethanimine (482.7 mg, 2.664 mmol), t-BuONa (388.6 mg,4.044 mmol), BINAP (135.2 mg, 0.2171 mmol), Pd₂(dba)₃ (181.5 mg, 0.1982mmol) and 1,4-dioxane (10 mL) was heated to 100° C. and stirred for 4 h.The reaction mixture was directly concentrated in vacuo, the residue wasdissolved with water (50 mL) and extracted with a mixed solvent ofDCM/MeOH (10/1 (v/v), 50 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound as a brown solid (650.6 mg), which was used directly inthe next step without further purification.

MS (ESI, pos.ion) m/z: 326.4 [M+H]⁺.

Step 5) 1,2-dimethyl-1H-benzo[d]imidazol-5-amine

N-(diphenylmethylene)-1,2-dimethyl-1H-benzo[d]imidazol-5-amine (650.6mg, 1.999 mmol) was dissolve in a solution of hydrogen chloride in EtOAc(10 mL, 40 mmol, 4 M). The reaction mixture was stirred at rt overnightand then washed with water (20 mL×3), the combined aqueous phases wereadjusted to pH=12 with NaOH powder, and then extracted with DCM/MeOH(10/1, 100 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH(v/v)=80/1) to give the titlecompound as a yellow solid (190 mg, yield 59%).

MS (ESI, pos.ion) m/z: 162.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.04 (d, J=8.4 Hz, 1H), 6.98 (d, J=1.9Hz, 1H), 6.66 (dd, J=8.4, 2.0 Hz, 1H), 3.63 (s, 3H), 2.53 (s, 3H).

Step 6)6-(4-((5-chloro-2-((1,2-dimethyl-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of 1,2-dimethyl-1H-benzo[a]imidazol-5-amine (100.4 mg,0.6228 mmol) and6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(217.8 mg, 0.6237 mmol) in 1,4-dioxane (10 mL) were added Cs₂CO₃ (608.2mg, 1.867 mmol), BINAP (38.6 mg, 0.0620 mmol) and Pd(OAc)₂ (14.5 mg,0.0646 mmol). The reaction solution was heated to 100° C. for 5 hoursunder N₂ atmosphere and concentrated in vacuo. The residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=40/1) to give thetitle compound as an off-white solid (145.4 mg, yield 49.3%).

MS (ESI, pos.ion) m/z: 474.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 474.1921 [M+H]⁺, calculated value forC₂₄H₂₅ClN₉ [M+H]⁺ is 474.1921;

¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 9.10 (s, 1H), 8.50 (d, J=2.1 Hz, 1H),7.99 (d, J=1.5 Hz, 1H), 7.92 (s, 1H), 7.85 (dd, J=9.1, 2.3 Hz, 1H), 7.46(dd, J=8.7, 1.7 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.00 (d, J=9.1 Hz, 1H),6.81 (d, J=7.8 Hz, 1H), 4.53 (d, J=13.3 Hz, 2H), 4.37-4.27 (m, 1H), 3.67(s, 3H), 3.10 (t, J=12.2 Hz, 2H), 2.47 (s, 3H), 1.99 (d, J=10.6 Hz, 2H),1.61 (qd, J=12.4, 3.7 Hz, 2H);

¹³CNMR (100 MHz, DMSO-d₆) δ (ppm): 159.0, 158.3, 156.7, 153.4, 152.6,152.0, 142.5, 140.0, 135.1, 131.3, 118.8, 114.7, 108.7, 108.5, 106.5,102.8, 94.8, 43.9, 30.6, 29.6, 13.5.

Example 496-(4-((5-chloro-2-((1,2-dimethyl-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(303.4 mg, 0.8664 mmol), 1,2-dimethyl-1H-benzo[d]imidazol-5-amine (145.6mg, 0.9032 mmol) and Cs₂CO₃ (841.3 mg, 2.582 mmol) in 1,4-dioxane (15mL) were added BINAP (50.7 mg, 0.0814 mmol) and Pd(OAc)₂ (19.0 mg,0.0846 mmol). The reaction solution was heated to 100° C. under N₂atmosphere and stirred overnight and then concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=40/1) to give the title compound as a yellow solid (167.4 mg,yield 40.7%).

MS (ESI, pos.ion) m/z: 475.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 475.1870 [M+H]⁺, calculated value forC₂₃H₂₄ClN₁₀ [M+H]⁺ is 475.1874;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.13 (s, 1H), 8.00 (d, J=1.4 Hz, 1H),7.93 (s, 1H), 7.87 (d, J=9.7 Hz, 1H), 7.46 (dd, J=8.7, 1.6 Hz, 1H), 7.43(d, J=9.7 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.62(d, J=10.1 Hz, 2H), 4.41-4.32 (m, 1H), 3.67 (s, 3H), 3.20 (t, J=12.3 Hz,2H), 2.47 (s, 3H), 2.04 (d, J=10.8 Hz, 2H), 1.66 (qd, J=12.6, 3.8 Hz,2H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 159.1, 158.7, 157.2, 153.9, 152.5,142.9, 135.6, 131.7, 131.6, 128.8, 118.0, 115.1, 111.6, 109.2, 108.9,103.2, 44.3, 31.0, 30.1, 13.9.

Example 506-(4-((5-chloro-2-((1-methyl-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(285.8 mg, 0.82 mmol) and 1-methyl-1H-benzo[a]imidazol-5-amine (149.1mg, 1.01 mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)₂ (38.3 mg, 0.17mmol), BINAP (98%, 106.0 mg, 0.17 mmol) and Cs₂CO₃ (98%, 554.2 mg, 1.67mmol). The reaction mixture was stirred at 100° C. overnight and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/40) to give the title compound as abeige solid (233.3 mg, yield 62%).

MS (ESI, pos. ion) m/z: 461.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 461.1740 [M+H]⁺, calculated value forC₂₂H₂₂ClN₁₀ [M+H]⁺ is 461.1717;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.22 (s, 1H), 8.24 (s, 1H), 8.07 (s,1H), 7.96 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.50 (dd, J=8.7, 1.6 Hz, 1H),7.44 (dd, J=9.2, 4.4 Hz, 2H), 6.89 (d, J=7.7 Hz, 1H), 4.66 (d, J=12.5Hz, 2H), 4.47-4.33 (m, 1H), 3.80 (s, 3H), 3.22 (t, J=12.3 Hz, 2H), 2.07(d, J=10.9 Hz, 2H), 1.67 (qd, J=12.5, 3.8 Hz, 2H);

¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 159.1, 158.7, 157.2, 153.9, 145.0,144.1, 135.9, 131.5, 130.5, 128.8, 117.9, 116.2, 111.6, 109.8, 109.7,103.3, 48.6, 44.4, 31.1, 31.0.

Example 516-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 1-(6-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol

To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (360.0 mg, 1.83 mmol)and 1-bromopropan-2-ol (500.0 mg, 3.60 mmol) in DMF (20 mL) was addedCs₂CO₃ (1.78 g, 5.46 mmol). The reaction was stirred at 100° C. for 6 h,then cooled down to rt, and quenched with water (50 mL) and theresulting mixture was extracted with EtOAc (80 mL×3). The combinedorganic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/PE (v/v)=1/1) to give the title compound as awhite solid (0.16 g, yield 34%).

MS (ESI, pos. ion) m/z: 256.0 [M+H]⁺.

Step 2)1-(6-((diphenylmethylene)amino)-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol

To a solution of 1-(6-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol(270.0 mg, 1.05 mmol), diphenylmethanimine (380.0 mg, 2.10 mmol),Pd₂(bda)₃ (100.0 mg, 0.10 mmol), BINAP (135.0 mg, 0.21 mmol) in1,4-dioxane (20 mL) was added t-BuONa (200.0 mg, 2.04 mmol). Thereaction was stirred under N₂ atmosphere at 100° C. overnight and thenconcentrated in vacuo. The residue was diluted with water (20 mL) andextracted with DCM (20 mL×3). The combined organic phases wereconcentrated in vacuo to give the compound as a yellow solid (236.6 mg,yield 63%).

MS (ESI, pos. ion) m/z: 357.1 [M+H]⁺.

Step 3) 1-(6-amino-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol

To a solution of1-(6-((diphenylmethylene)amino)-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol(340.0 mg, 0.95 mmol) in 1,4-dioxane (20 mL) was added a solution of HClin EtOAc (20 mL, 60 mmol, 3 M) at rt dropwise. The reaction mixture wasstirred at rt overnight, then quenched with water (20 ml), and adjustedto pH=10 with a saturated Na₂CO₃ aqueous solution, then concentrated invacuo. The residue was diluted with DCM (10 mL) and MeOH (10 mL) andthen filtered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the compound as a brown solid (110.0 mg, yield 60%).

MS (ESI, pos. ion) m/z: 193.1 [M+H]⁺.

Step 4)6-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of Pd(OAc)₂ (15.0 mg, 0.065 mmol), BINAP (40.0 mg, 0.062mmol), 1-(6-amino-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol (120.0 mg,0.62 mmol), and6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(100.0 mg, 0.29 mmol) in 1,4-dioxane (30 mL) was added Cs₂CO₃ (615.0 mg,1.89 mmol). The reaction was stirred at 100° C. under N₂ atmosphereovernight and then concentrated in vacuo. The residue was purified bysilica gel column chromatography (MeOH/DCM (v/v)=1/40) to give thecompound as a white solid (25.0 mg, yield 8%).

MS (ESI, pos. ion) m/z: 505.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 505.1991 [M+H]⁺, calculated value forC₂₄H₂₆ClN₁₀O [M+H]⁺ is 505.1980;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.41 (s, 1H), 8.57 (s, 1H), 8.49 (s,1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.1 Hz, 1H),6.99 (d, J=9.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.11 (s, 1H), 4.47 (d,J=11.0 Hz, 2H), 4.34 (s, 1H), 4.17 (d, J=12.1 Hz, 1H), 4.08-3.97 (m,2H), 3.05 (t, J=12.7 Hz, 2H), 1.93 (d, J=10.1 Hz, 2H), 1.70-1.57 (m,2H), 1.07 (d, J=5.4 Hz, 3H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 159.4, 158.7, 157.3, 153.8, 153.1,151.4, 146.1, 140.4, 138.0, 133.2, 126.8, 119.0, 109.2, 107.0, 104.3,95.2, 65.6, 52.2, 48.1, 44.1, 31.0, 21.3.

Example 526-(4-((5-chloro-2-((3-(2-hydroxypropyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 1-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol

To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (360.0 mg, 1.83 mmol)and 1-bromopropan-2-ol (500.0 mg, 3.60 mmol) in DMF (20 mL) was addedCs₂CO₃ (1.78 g, 5.46 mmol). The reaction was stirred at 100° C. for 6 h,then cooled down to rt, and quenched with water (50 mL). The resultingmixture was extracted with EtOAc (80 mL×3). The combined organic phaseswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/1) to give the title compound as a white solid (180.0 mg, yield39%).

MS (ESI, pos. ion) m/z: 256.0 [M+H]⁺.

Step 2)1-(6-((diphenylmethylene)amino)-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol

To a solution of 1-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol(170.0 mg, 0.66 mmol), diphenylmethanimine (240.0 mg, 1.32 mmol),Pd₂(bda)₃ (63.0 mg, 0.067 mmol), BINAP (85.0 mg, 0.13 mmol) in1,4-dioxane (10 mL) was added t-BuONa (130.0 mg, 1.33 mmol). Thereaction was stirred at 100° C. under N₂ atmosphere for 6 hours and thenconcentrated in vacuo. The residue was diluted with water (20 mL) andthe resulting mixture was extracted with DCM (20 mL×3). The combinedorganic phases were concentrated in vacuo to give the compound as ayellow solid (236.6 mg, yield 100%).

MS (ESI, pos. ion) m/z: 357.4 [M+H]⁺.

Step 3) 1-(6-amino-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol

To a solution of1-(6-((diphenylmethylene)amino)-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol(340.0 mg, 0.95 mmol) in 1,4-dioxane (20 mL) was added a solution of HClin EtOAc (20 mL, 60 mmol, 3 M) dropwise at rt. The reaction mixture wasstirred at rt overnight, then quenched with water (20 ml), and adjustedto pH=10 with a saturated Na₂CO₃ aqueous solution, then the resultingmixture was concentrated in vacuo. The residue was diluted in DCM (10mL) and MeOH (10 mL) and then filtered. The filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/CH₂Cl₂ (v/v)=1/10) to give the title compound as a brown solid(110.0 mg, yield 60%).

MS (ESI, pos. ion) m/z: 193.1 [M+H]⁺.

Step 4)6-(4-((5-chloro-2-((3-(2-hydroxypropyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of Pd(OAc)₂ (12.1 mg, 0.053 mmol), BINAP (33.2 mg, 0.052mmol), 1-(6-amino-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol (101.2 mg,0.53 mmol), and6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(180.8 mg, 0.52 mmol) in 1,4-dioxane (30 mL) was added Cs₂CO₃ (431.2 mg,1.32 mmol). The reaction was stirred at 100° C. under N₂ overnight andthen concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (MeOH/CH₂Cl₂ (v/v)=1/40) to give the compound as awhite solid (28.3 mg, yield 11%).

MS (ESI, pos. ion) m/z: 505.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 505.1963 [M+H]⁺, calculated value forC₂₄H₂₆ClN₁₀O [M+H]⁺ is 505.1980;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.38 (s, 1H), 8.58 (s, 1H), 8.49 (d,J=14.5 Hz, 2H), 8.27 (s, 1H), 7.96 (s, 1H), 7.85 (dd, J=9.0, 1.7 Hz,1H), 7.01 (d, J=9.1 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 5.01 (d, J=4.3 Hz,1H), 4.54 (d, J=11.7 Hz, 2H), 4.37-4.25 (m, 1H), 4.18 (d, J=9.9 Hz, 1H),4.12-4.02 (m, 2H), 3.05 (t, J=12.5 Hz, 2H), 2.03-1.98 (m, 2H), 1.64-1.58(m, 2H), 1.07 (d, J=5.6 Hz, 3H);

¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 159.4, 158.7, 157.2, 153.9, 153.1,146.5, 142.9, 140.5, 137.6, 134.9, 133.5, 130.1, 119.3, 117.9, 107.0,95.3, 65.0, 50.6, 44.3, 40.5, 31.0, 21.4.

Example 536-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 1-(6-bromo-1H-pyrrolo[3,2-b]pyridin-1-yl)propan-2-ol

To a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (1.01 g, 5.13 mmol)and 1-bromopropan-2-ol (2.14 g, 15.0 mmol) in DMF (10 mL) was addedCs₂CO₃ (4.97 g, 15.3 mmol) and the mixture was stirred at 100° C.overnight. The solution was diluted with EtOAc (100 mL), washed withwater (100 mL) and dried over anhydrous Na₂SO₄, filtered, and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/1) to give the title compound as yellowoil (1.22 g, yield 93.3%).

MS (ESI, pos. ion) m/z: 255.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.32 (d, J=1.8 Hz, 1H), 7.80 (d, J=0.9Hz, 1H), 7.27 (d, J=3.3 Hz, 1H), 6.44 (d, J=3.2 Hz, 1H), 4.22-4.16 (m,1H), 4.08 (dd, J=14.5, 3.3 Hz, 1H), 3.95 (dd, J=14.5, 8.0 Hz, 1H), 3.46(s, 1H), 1.28 (d, J=6.3 Hz, 3H).

Step 2)1-(6-((diphenylmethylene)amino)-1H-pyrrolo[3,2-b]pyridin-1-yl)propan-2-ol

To a solution of1-(6-((diphenylmethylene)amino)-1H-pyrrolo[3,2-b]pyridin-1-yl)propan-2-ol(1.1 g, 4.30 mmol) and diphenylmethanimine (935 mg, 5.16 mmol) in1,4-dioxane (20 mL) were added BINAP (270 mg, 0.433 mmol), Pd₂(dba)₃(391 mg, 0.427 mmol) and Cs₂CO₃ (2.81 g, 8.62 mmol). The reaction wasstirred at 105° C. under N₂ atmosphere overnight and then concentratedin vacuo. The residue was diluted with water (50 mL) and the resultingmixture was extracted with DCM (100 mL×3). The combined organic phaseswere washed with brine (50 mL×3), dried over anhydrous Na₂SO₄,concentrated in vacuo to give the title compound as a brown solid (1.5g, yield 98%).

MS (ESI, pos. ion) m/z: 356.1 [M+H]⁺.

Step 3) 1-(6-amino-1H-pyrrolo[3,2-b]pyridin-1-yl)propan-2-ol

To a solution of1-(6-((diphenylmethylene)amino)-1H-pyrrolo[3,2-b]pyridin-1-yl)propan-2-ol(1.5 g, 4.20 mmol) in 1,4-dioxane (20 mL) was added concentratedhydrogen chloride (6 mL, 72 mmol, 12 M). The reaction mixture wasstirred at rt for 2 h and then concentrated in vacuo. The residue wasadjusted to pH=10 with a saturated NaHCO₃ aqueous solution, thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography ((a solution of NH₃ in MeOH (7M))/DCM (v/v)=1/20) to givethe title compound as a brown solid (480 mg, yield 59.0%).

MS (ESI, pos. ion) m/z: 192.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.83 (d, J=1.6 Hz, 1H), 7.23 (d,J=3.1 Hz, 1H), 6.96 (s, 1H), 6.29 (d, J=3.0 Hz, 1H), 4.09 (d, J=4.5 Hz,1H), 3.95-3.91 (m, 1H), 3.17 (d, J=3.0 Hz, 2H), 1.02 (d, J=5.5 Hz, 3H).

Step 4)6-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(101 mg, 0.289 mmol) and1-(6-amino-1H-pyrrolo[3,2-b]pyridin-1-yl)propan-2-ol (82 mg, 0.428 mmol)in 1,4-dioxane (10 mL) were added Cs₂CO₃ (94 mg, 0.288 mmol), BINAP (17mg, 0.027 mmol) and Pd(OAc)₂ (6 mg, 0.026 mmol). The mixture was stirredat 105° C. under N₂ atmosphere for 3 hours and then concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM(v/v)=1/40) to give the title compound as a yellow solid (65mg, yield 44.6%).

MS (ESI, pos. ion) m/z: 504.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 504.2039 [M+H]⁺, calculated value forC₂₅H₂₇ClN₉O [M+H]⁺ is 504.1949;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.44 (s, 1H), 8.39 (d, J=1.5 Hz, 1H),8.02 (s, 1H), 7.89 (s, 1H), 7.59 (dd, J=9.0, 2.0 Hz, 1H), 6.61 (d, J=9.0Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.14 (d, J=7.4 Hz, 1H), 4.33 (d, J=13.4Hz, 2H), 4.27-4.23 (m, 1H), 4.19 (dd, J=10.0, 6.6 Hz, 1H), 4.10 (dd,J=14.5, 3.4 Hz, 1H), 4.01 (dd, J=14.5, 7.8 Hz, 1H), 3.19 (t, J=12.6 Hz,2H), 2.15 (d, J=10.3 Hz, 2H), 1.52 (dd, J=23.1, 11.3 Hz, 2H), 1.27 (d,J=6.2 Hz, 3H);

¹³C NMR (150 MHz, CDCl₃) δ (ppm): 159.2, 158.5, 157.2, 153.1, 152.9,142.4, 140.0, 137.7, 131.5, 130.8, 129.8, 118.8, 109.0, 106.0, 105.2,102.4, 96.4, 67.3, 54.3, 48.1, 43.6, 31.6, 21.0.

Example 546-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)propan-2-ol

To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (1.01 g, 5.13 mmol)and 1-bromopropan-2-ol (2.13 g, 15.3 mmol) in DMF (20 mL) was addedCs₂CO₃ (5.00 g, 15.3 mmol) and the mixture was stirred at 100° C. for 4h. The solution was diluted with EtOAc (100 mL), then washed with water(100 mL) and dried over anhydrous Na₂SO₄, filtered and then concentratedin vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc(v/v)=1/1) to give the title compound as yellow oil (1.24 g,yield 94.8%).

MS (ESI, pos. ion) m/z: 256.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.28 (d, J=2.0 Hz, 1H), 8.03 (d, J=2.1Hz, 1H), 7.23 (d, J=3.4 Hz, 1H), 6.40 (d, J=3.5 Hz, 1H), 4.35-4.30 (m,1H), 4.26-4.20 (m, 1H), 4.16 (m, 1H), 3.93 (d, J=3.8 Hz, 1H), 1.22 (d,J=6.2 Hz, 3H).

Step 2)1-(5-((diphenylmethylene)amino)-1H-pyrrolo[2,3-b]pyridin-1-yl)propan-2-ol

To a solution of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)propan-2-ol(1.24 g, 4.86 mmol) and diphenylmethanimine (1.04 g, 5.74 mmol) in1,4-dioxane (20 mL) were added BINAP (303 mg, 0.486 mmol), Pd(OAc)₂ (106mg, 0.472 mmol) and Cs₂CO₃ (3.18 g, 9.76 mmol). The reaction was stirredat 105° C. under N₂ atmosphere overnight and then concentrated in vacuo.The residue was diluted with water (50 mL), and the resulting mixturewas extracted with DCM (100 mL×3). The combined organic phases werewashed with brine (50 mL×3), dried over anhydrous Na₂SO₄, concentratedin vacuo to give the title compound as a brown solid (1.70 g, yield98.0%).

MS (ESI, pos. ion) m/z: 356.1 [M+H]⁺.

Step 3) 1-(5-amino-1H-pyrrolo[2,3-b]pyridin-1-yl)propan-2-ol

To a solution of1-(5-((diphenylmethylene)amino)-1H-pyrrolo[2,3-b]pyridin-1-yl)propan-2-ol(1.7 g, 4.80 mmol) in 1,4-dioxane (20 mL) was added concentratedhydrogen chloride (6 mL, 72 mol, 12 M). The reaction mixture was stirredat rt for 3 h and then concentrated in vacuo. The residue was adjustedto pH=10 with a saturated NaHCO₃ aqueous solution, then concentrated invacuo. The residue was purified by silica gel column chromatography((MeOH/DCM (v/v)=1/30) to give the title compound as a brown solid (180mg, yield 20.0%).

MS (ESI, pos. ion) m/z: 192.1 [M+H]⁺.

Step 4)6-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(59 mg, 0.169 mmol) and1-(5-amino-1H-pyrrolo[2,3-b]pyridin-1-yl)propan-2-ol (50 mg, 0.261 mmol)in 1,4-dioxane (10 mL) were added Cs₂CO₃ (117 mg, 0.359 mmol), BINAP (10mg, 0.016 mmol) and Pd(OAc)₂ (4 mg, 0.017 mmol). The mixture was heatedto reflux and stirred under N₂ atmosphere for 2 hours and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM(v/v)=1/40) to give the title compound as ayellow solid (50 mg, yield 58.7%).

MS (ESI, pos. ion) m/z: 504.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 504.2050 [M+H]⁺, calculated value forC₂₅H₂₇ClN₉O [M+H]⁺ is 504.1949;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.40 (d, J=1.8 Hz, 1H), 8.30 (d, J=2.1Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.89 (s, 1H), 7.60 (dd, J=9.0, 2.3 Hz,1H), 7.30 (s, 1H), 7.19 (d, J=3.4 Hz, 1H), 6.63 (d, J=9.0 Hz, 1H), 6.39(d, J=3.4 Hz, 1H), 5.13 (d, J=7.2 Hz, 1H), 4.40 (d, J=13.5 Hz, 2H),4.34-4.29 (m, 1H), 4.26-4.14 (m, 3H), 3.10 (t, J=11.7 Hz, 2H), 2.17 (d,J=12.4 Hz, 2H), 1.53-1.47 (m, 2H), 1.22 (d, J=6.2 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃) δ (ppm): 159.2, 158.9, 157.2, 153.3, 152.9,144.8, 140.0, 137.5, 130.7, 129.9, 121.9, 120.8, 118.7, 105.9, 104.7,99.3, 96.4, 67.8, 54.4, 48.5, 43.8, 31.7, 20.8.

Example 556-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) tert-butyl (mesitylsulfonyl)oxycarbamate

To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (20.01 g,91.50 mmol) and tert-butyl hydroxycarbamate (12.24 g, 91.93 mmol) inEtOAc (200 mL) was added triethylamine (15.4 mL, 110 mmol) dropwise at−10° C. After addition, the reaction mixture was warmed up to 0° C. andstirred for 2 h, then quenched with water (100 mL) and separated. Theseparated organic layer was washed with water (200 mL×3), thenconcentrated in vacuo. The residue was used to the next step withoutfurther purification.

MS (ESI, pos. ion) m/z: 338.2 [M+23]⁻.

Step 2) O-(mesitylsulfonyl)hydroxylamine

To a solution of tert-butyl (mesitylsulfonyl)oxycarbamate (28.86 g,91.50 mmol) in EtOAc (200 mL) was added concentrated sulfuric acid (9.0mL, 164.7 mmol) dropwise. After addition, the reaction mixture wasstirred at 0° C. overnight, neutralized by a saturated sodium carbonatesolution, then separated. The separated organic layer was washed withwater (300 mL) then concentrated in vacuo. The residue was used to thenext step without further purification.

Step 3) 1,2-diamino-4-bromopyridin-1-ium 2,4,6-trimethylbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (19.70 g, 91.50 mmol)in EtOAc (400 mL) was added 4-bromopyridin-2-amine (7.95 g, 45.8 mmol)at 5° C. The reaction mixture was stirred at 5° C. for 1 h and filtered.The filter cake was washed with EtOAc (20 mL×3), then dried in vacuo togive the title compound as a white solid (13.70 g, 77% for 3 steps).

MS (ESI, pos. ion) m/z: 188.1 [M₁]⁺;

MS (ESI, neg. ion) m/z: 199.1 [M₂]⁻.

Step 4) ethyl 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

To a solution of 1,2-diamino-4-bromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (3.98 g, 10.2 mmol) in pyridine (30 mL)was added ethyl 2-chloro-2-oxo-acetate (2.45 mL, 21.9 mmol) at 0° C. Thereaction mixture was stirred at rt for 30 min, then move to 100° C. andstirred overnight, and then concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc/PE (v/v)=1/4) togive the title compound as a white solid (0.42 g, 15%).

MS (ESI, pos. ion) m/z: 269.9 [M+H]⁺.

Step 5) 2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of ethyl7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (0.30 g, 1.1 mmol)in THF (11 mL) was added methylmagnesium bromide (3.0 M solution indiethyl ether, 1.9 mL, 5.7 mmol) dropwise at −78° C. under N₂atmosphere. After addition, the reaction mixture was warmed up to 0° C.,stirred overnight and quenched with a cold saturated ammonium chloridesolution, then extracted with EtOAc (10 mL×2). The combined organicphases were dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc/PE (v/v)=1/1) togive the title compound as a white solid (0.19 g, 67%).

MS (ESI, pos. ion) m/z: 256.0 [M+H]⁺.

Step 6)2-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol (0.19 g, 0.74mmol) and diphenylmethanimine (0.17 g, 0.94 mmol) in 1,4-dioxane (5 mL)were added Pd₂(dba)₃ (0.068 g, 0.074 mmol), BINAP (0.046 g, 0.074 mmol)and Cs₂CO₃ (0.48 g, 1.5 mmol). The reaction mixture was stirred at 100°C. overnight under N₂ atmosphere and concentrated in vacuo. The residuewas dissolved in DCM (20 mL), the resulted mixture was washed with water(15 mL×2). The organic phase was concentrated in vacuo to give the titlecompound as brown oil, which was used to the next step without furtherpurification.

MS (ESI, pos. ion) m/z: 357.1 [M+H]⁺.

Step 7) 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of2-[7-(benzhydrylideneamino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]propan-2-ol(0.26 g, 0.73 mmol) in DCM (5 mL) was added a solution of HCl in EtOAc(3M, 2.5 mL, 7.5 mmol). The reaction mixture was stirred at rt for 1 hand concentrated in vacuo. The residue was adjusted to pH=9 with asolution of NaOH (1M) and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as a yellow solid (0.12 g, 86% for 2 steps).

MS (ESI, pos. ion) m/z: 193.1 [M+H]⁺.

Step 8)6-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(102.3 mg, 0.29 mmol) and 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol (81.2 mg, 0.42 mmol) in 1,4-dioxane (8 mL) were addedPd(OAc)₂ (6.8 mg, 0.03 mmol), BINAP (18.2 mg, 0.03 mmol) and Cs₂CO₃(188.3 mg, 0.58 mmol). The reaction mixture was stirred at 100° C.overnight under N₂ atmosphere and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (MeOH/DCM (v/v)=1/20) togive the title compound as a creamy white solid (138.1 mg, 93.4%).

MS (ESI, pos. ion) m/z: 506.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 506.1943 [M+H]⁺; calculated value forC₂₃H₂₅ClN₁₁O [M+H]⁺ is 506.1932;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.88 (s, 1H), 8.69 (d, J=7.4 Hz, 1H),8.31 (d, J=1.5 Hz, 1H), 8.10 (s, 1H), 7.89 (d, J=9.7 Hz, 1H), 7.45 (d,J=9.8 Hz, 1H), 7.33 (dd, J=7.5, 2.0 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H),5.04 (s, 1H), 4.64 (d, J=12.2 Hz, 2H), 4.47-4.32 (m, 1H), 3.18 (d, J=5.2Hz, 2H), 2.06 (d, J=12.2 Hz, 2H), 1.76-1.65 (m, 2H), 1.53 (s, 6H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 172.7, 159.2, 157.9, 157.4, 153.7,152.0, 142.5, 131.6, 128.9, 128.6, 117.9, 111.6, 108.4, 105.6, 99.5,68.6, 48.7, 44.3, 30.9, 30.2.

Example 566-(4-((5-chloro-2-((2-(2-hydroxypropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 1-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-one

To a solution of ethyl 2-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate (1.06 g, 3.8 mmol) in THF (12 mL) was added methylmagnesiumbromide (3.0 M solution in diethyl ether, 1.2 mL, 3.6 mmol) dropwise at−78° C. under N₂ atmosphere. After addition, the reaction mixture waswarmed up to −30° C. and stirred for 4 h, and then quenched with a coldsaturated ammonium chloride solution. The resulting mixture wasextracted with EtOAc (15 mL×2). The combined organic phases were driedover Na₂SO₄ and concentrated in vacuo. The residue was purified by asilica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the titlecompound as a white solid (78.0 mg, 8%).

MS (ESI, pos. ion) m/z: 254.0 [M+H]⁺.

Step 2) 1-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of1-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-one (100 mg, 0.39mmol) in EtOH (10 mL) was added sodium borohydride (31.5 mg, 0.83 mmol)at 0° C. After addition, the reaction mixture was stirred at 20° C.overnight, quenched with a cold saturated ammonium chloride solution andextracted with EtOAc (15 mL×3). The combined organic phases were driedover Na₂SO₄ and concentrated in vacuo. The residue was purified by asilica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the titlecompound as a white solid (99.5 mg, 99%).

MS (ESI, pos.ion) m/z: 256.1 [M+H]⁺.

Step 3)1-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of1-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol (100 mg, 0.39mmol) and diphenylmethanimine (88.1 mg, 0.49 mmol) in 1,4-dioxane (8 mL)were added Pd₂(dba)₃ (35.4 mg, 0.04 mmol), BINAP (24.3 mg, 0.04 mmol)and Cs₂CO₃ (257.1 mg, 0.79 mmol). The reaction mixture was stirred at100° C. under N₂ atmosphere overnight and concentrated in vacuo. Theresidue was dissolved in DCM (20 mL) and washed with water (15 mL×2).The organic phase was concentrated in vacuo to give the title compoundas brown oil, which was used to the next step without furtherpurification.

MS (ESI, pos.ion) m/z: 357.3 [M+H]⁺.

Step 4) 1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of1-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol(139.2 mg, 0.39 mmol) in DCM (3 mL) was added a solution of HCl in EtOAc(3 M, 1.5 mL, 4.5 mmol). The reaction mixture was stirred at rt for 1 hand concentrated in vacuo. The residue was neutralized to pH=9 with aNaOH aqueous solution (1M) and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as a yellow solid (69.5 mg, 93% for 2 steps).

MS (ESI, pos. ion) m/z: 193.2 [M+H]⁺.

Step 5)6-(4-((5-chloro-2-((2-(2-hydroxypropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(52.5 mg, 0.15 mmol) and1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol (37.2 mg, 0.19mmol) in 1,4-dioxane (5 mL) were added Pd(OAc)₂ (3.3 mg, 0.02 mmol),BINAP (9.1 mg, 0.02 mmol) and Cs₂CO₃ (97.5 mg, 0.30 mmol). The reactionmixture was stirred at 95° C. for 6 h under N₂ atmosphere andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as acreamy white solid (58.9 mg, 78%).

MS (ESI, pos. ion) m/z=506.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 506.1956. [M+H]⁺; calculated value forC₂₃H₂₅ClN₁₁O [M+H]⁺ is 506.1932;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.89 (s, 1H), 8.65 (d, J=7.4 Hz, 1H),8.31 (s, 1H), 8.09 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.44 (d, J=9.7 Hz,1H), 7.28 (dd, J=7.4, 2.0 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H), 4.71 (d,J=4.6 Hz, 1H), 4.64 (d, J=12.8 Hz, 2H), 4.49-4.31 (m, 1H), 4.16-4.02 (m,1H), 3.25 (t, J=20.3, 8.1 Hz, 2H), 2.78 (ABX, J=6.4, 6.8, 14.0 Hz, 2H),2.06 (d, J=11.6 Hz, 2H), 1.79-1.58 (m, 2H), 1.10 (d, J=6.1 Hz, 3H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 165.1, 159.1, 157.9, 157.4, 153.8,152.0, 142.5, 131.5, 128.8, 128.3, 117.9, 111.6, 108.2, 105.6, 99.1,65.9, 48.8, 44.3, 38.8, 30.9, 23.7.

Example 576-(4-((5-chloro-2-((2-(2-hydroxypropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(24.3 mg, 0.07 mmol) and 1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol (18.5 mg, 0.10 mmol) in 1,4-dioxane (2 mL) were addedPd(OAc)₂ (1.9 mg, 0.01 mmol), BINAP (4.8 mg, 0.01 mmol) and Cs₂CO₃ (48.2mg, 0.15 mmol). The reaction mixture was stirred at 90° C. overnightunder N₂ atmosphere and concentrated in vacuo. The residue was purifiedby a silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give thetitle compound as a yellow solid (25.5 mg, 73%).

MS (ESI, pos. ion) m/z: 505.2 [M+H]⁺.

HRMS (ESI, pos. ion) m/z: 505.1943 [M+H]⁺, calculated value forC₂₄H₂₆ClN₁₀O [M+H]⁺ is 505.1980;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.87 (s, 1H), 8.64 (d, J=7.3 Hz, 1H),8.51 (s, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.27(d, J=6.4 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 4.69(d, J=4.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 2H), 4.46-4.26 (m, 1H), 4.17-4.00(m, 1H), 3.13 (t, J=12.6 Hz, 2H), 2.78 (ABX, J=6.2, 6.8, 14.0 Hz, 2H),2.12-1.88 (m, 2H), 1.76-1.54 (m, 2H), 1.10 (d, J=5.9 Hz, 3H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 165.1, 159.5, 157.9, 157.3, 153.7,153.1, 152.1, 142.5, 140.4, 128.3, 119.2, 108.1, 107.0, 105.5, 99.1,95.3, 65.9, 49.0, 44.3, 31.0, 23.7.

Example 58 methyl2-(7-((5-chloro-4-((1-(6-cyanopyridazin-3-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(40.1 mg, 0.12 mmol) and methyl2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-ypacetate (33.1 mg, 0.16mmol) in 1,4-dioxane (2 mL) were added Pd(OAc)₂ (1.8 mg, 0.008 mmol),BINAP (5.6 mg, 0.009 mmol) and Cs₂CO₃ (94.1 mg, 0.29 mmol). The reactionmixture was stirred at 100° C. overnight under N₂ atmosphere andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as abeige solid (22.6 mg, 38%).

MS (ESI, pos. ion) m/z: 520.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 520.1757 [M+H]⁺, calculated value forC₂₃H₂₃ClN₁₁O₂ [M+H]⁺ is 520.1725;

¹H NMR (400 MHz, CDCl₃+CD₃OD): δ (ppm) 8.29 (d, J=7.3 Hz, 1H), 8.21 (s,1H), 7.90 (s, 1H), 7.43 (d, J=9.5 Hz, 1H), 7.08 (d, J=6.7 Hz, 1H), 6.93(d, J=9.6 Hz, 1H), 4.47 (d, J=12.8 Hz, 2H), 4.36-4.31 (m, 1H), 3.85 (s,2H), 3.67 (s, 3H), 3.40 (t, J=12.3 Hz, 2H), 2.25 (d, J=11.8 Hz, 2H),1.62-1.54 (m, 2H).

¹³C NMR (150 MHz, CDCl₃+CD₃OD): δ (ppm) 169.8, 160.4, 158.5, 153.0,152.4, 142.1, 130.8, 130.0, 129.0, 127.7, 116.9, 110.3, 108.6, 106.3,99.9, 52.5, 43.6, 34.8, 31.4, 29.8.

Example 596-(4-((5-chloro-2-((2-(2-fluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(201.4 mg, 0.40 mmol) in DCM (15 mL) was added DAST (0.3 mL, 2.27 mmol)dropwise at −78° C. under N₂ atmosphere. The reaction mixture wasstirred at −78° C. for 1 h, then warmed to rt and stirred overnight, andthen adjusted to pH=9 with a saturated NaHCO₃ aqueous solution at 0° C.The reaction mixture was extracted with DCM (50 mL×2). The combinedorganic phases were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/55) to give the title compound as a white solid (176 mg, 87.0%).

MS (ESI, pos.ion) m/z: 507.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 507.1825 [M+H]⁺, calculated value forC₂₄H₂₅ClFN₁₀ [M+H]⁺ is 507.1936;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.42 (d, J=2.0 Hz, 1H), 8.38 (d, J=7.4Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.99 (s, 1H), 7.62 (dd, J=9.0, 2.2 Hz,1H), 7.31 (s, 1H), 7.06 (dd, J=7.4, 2.2 Hz, 1H), 6.66 (d, J=9.1 Hz, 1H),5.25 (d, J=7.3 Hz, 1H), 4.44 (d, J=13.6 Hz, 2H), 4.37-4.27 (m, 1H),3.33-3.26 (m, 2H), 2.25 (d, J=9.6 Hz, 2H), 1.90 (s, 3H), 1.85 (s, 3H),1.63-1.53 (m, 2H);

¹³C NMR (150 MHz, CDCl₃): δ (ppm) 168.9 (d, J=23.3 Hz) 159.3 (s), 157.3(d, J=12.1 Hz), 153.2 (s), 152.9 (s), 152.5 (s), 141.5 (s), 140.1 (s),128.0 (s), 118.7 (s), 108.5 (s), 106.9 (s), 105.9 (s), 100.9 (s), 96.6(s), 92.8 (s), 91.7 (s), 48.7 (s), 43.8 (s), 31.6 (s), 27.3 (s), 27.2(s).

Example 606-(4-((5-chloro-2-((1-(cyclopropylmethyl)-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) N¹-(cyclopropylmethyl)-4-nitrobenzene-1,2-diamine

To a solution of 2-fluoro-5-nitro-aniline (607.8 mg, 3.89 mmol) andpotassium carbonate (824.2 mg, 5.96 mmol) in DMSO (10 mL) was addedcyclopropylmethanamine (376.4 mg, 5.29 mmol). The mixture was placed ina sealed tube and stirred at 100° C. overnight. The mixture was cooleddown to rt and diluted with water (80 mL), then extracted with EtOAc (80mL×3). The combined organic phases were washed with brine (50 mL×5),dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bya silica gel column chromatography (EtOAc/PE (v/v)=1/3) to give thetitle compound as a brown solid (640 mg, 79.3%). MS (ESI, pos.ion) m/z:208.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃): δ (ppm) 7.81 (dd, J=8.8, 1.7 Hz, 1H), 7.62 (d,J=1.7 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.41 (s, 1H), 3.40 (s, 2H),3.07-3.05 (m, 2H), 1.18-1.12 (m, 1H), 0.62 (q, J=5.0 Hz, 2H), 0.30 (q,J=4.8 Hz, 2H).

Step 2) 1-(cyclopropylmethyl)-5-nitro-1H-benzo[d][1,2,3]triazole

To a solution of N¹-(cyclopropylmethyl)-4-nitro-benzene-1,2-diamine(580.0 mg, 2.80 mmol) in acetic acid (6 mL) was added a solution ofsodium nitrite in water (2 M, 3 mL, 6 mmol). The reaction mixture wasstirred at rt overnight and concentrated in vacuo. The residue wasadjusted to pH=8 with a saturated Na₂CO₃ aqueous solution and extractedwith DCM (50 mL×2). The combined organic phases were dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (EtOAc/PE (v/v)=1/5) to give the title compound asa yellow solid (520 mg, 85.1%).

MS (ESI, pos.ion) m/z: 219.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.97 (d, J=1.7 Hz, 1H), 8.37 (dd,J=9.1, 1.9 Hz, 1H), 7.70 (d, J=9.1 Hz, 1H), 4.58 (d, J=7.2 Hz, 2H),1.46-1.36 (m, 1H), 0.70 (q, J=5.9 Hz, 2H), 0.52 (q, J=5.3 Hz, 2H).

Step 3) 1-(cyclopropylmethyl)-1H-benzo[d][1,2,3]triazol-5-amine

To a solution of 1-(cyclopropylmethyl)-5-nitro-benzotriazole (520 mg,2.3830 mmol) in MeOH (20 mL) was added Pd/C (500 mg, 10%). The reactionmixture was stirred at rt under a H2 atmosphere overnight and filteredthrough a Celite pad. The filter cake was washed with MeOH (50 mL), andthe filtrate was concentrated in vacuo. The residue was purified by aflash column chromatography (MeOH/DCM (v/v)=1/35) to give the titlecompound as a red brown solid (350 mg, 78.0%).

MS (ESI, pos.ion) m/z: 189.3 [M+H]⁺.

Step 4)6-(4-((5-chloro-2-((1-(cyclopropylmethyl)-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(607.4 mg, 1.74 mmol) and 1-(cyclopropylmethyl)benzotriazol-5-amine (350mg, 1.86 mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)₂ (39.2 mg,0.175 mmol), BINAP (105.4 mg, 0.1693 mmol) and Cs₂CO₃ (1.134 g, 3.480mmol). The reaction mixture was sittred at reflux for 4 h andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/50) to give the title compound as anoff-white solid (610 mg, 70%).

MS (ESI, pos.ion) m/z: 501.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 501.2003 [M+H]⁺; calculated value forC₂₅H₂₆ClN₁₀ [M+H]⁺ is 501.2030;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.52 (s, 1H), 8.62 (s, 1H), 8.51 (d,J=2.0 Hz, 1H), 8.01 (s, 1H), 7.85 (dd, J=9.1, 2.2 Hz, 1H), 7.80 (d,J=9.0 Hz, 1H), 7.70 (dd, J=9.0, 1.2 Hz, 1H), 7.01 (t, J=8.6 Hz, 2H),4.58 (d, J=13.2 Hz, 2H), 4.53 (d, J=7.1 Hz, 2H), 4.42-4.31 (m, 1H), 3.12(t, J=12.5 Hz, 2H), 2.03 (d, J=11.0 Hz, 2H), 1.68-1.58 (m, 2H),1.39-1.29 (m, 1H), 0.56-0.52 (m, 2H), 0.47-0.45 (m, 2H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 158.9, 158.0, 156.7, 153.4, 152.6,146.0, 139.9, 137.3, 128.5, 121.6, 118.7, 110.2, 106.4, 105.5, 103.6,94.8, 51.8, 48.4, 43.8, 30.6, 11.2, 3.8.

Example 616-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 1-((2-amino-4-nitrophenyl)amino)propan-2-ol

To a solution of 2-fluoro-5-nitro-aniline (408.6 mg, 2.62 mmol) andpotassium carbonate (714.4 mg, 5.17 mmol) in DMSO (4 mL) was added1-aminopropan-2-ol (294.4 mg, 3.92 mmol). The mixture was placed in asealed tube and stirred at 100° C. overnight. The mixture was cooleddown to rt and diluted with water (60 mL), then extracted with EtOAc(100 mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/33) to give the title compound as abrown solid (520 mg, 94.1%).

MS (ESI, pos.ion) m/z: 212.2 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ (ppm) 7.51 (dd, J=8.8, 2.5 Hz, 1H), 7.41(d, J=2.5 Hz, 1H), 6.50 (d, J=8.9 Hz, 1H), 5.88 (t, J=5.3 Hz, 1H), 5.15(s, 2H), 4.81 (d, J=4.7 Hz, 1H), 3.89-3.83 (m, 1H), 3.17-3.08 (m, 2H),1.13 (d, J=6.2 Hz, 3H).

Step 2) 1-(5-nitro-1H-benzo[d]imidazol-1-yl)propan-2-ol

A mixture of 1-(2-amino-4-nitro-anilino)propan-2-ol (520 mg, 2.46 mmol)and trimethoxymethane (10 mL) was heated to reflux and stirred for 5 h,then concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (EtOAc/PE (v/v)=4/1) to give the title compound asa reddish-brown solid (310 mg, 56.9%).

MS (ESI, pos.ion) m/z: 222.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.54 (d, J=1.9 Hz, 1H), 8.46 (s, 1H),8.17 (dd, J=8.9, 2.0 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 5.04 (d, J=4.9 Hz,1H), 4.34 (dd, J=14.2, 3.4 Hz, 1H), 4.15 (dd, J=14.2, 7.6 Hz, 1H),4.04-3.95 (m, 1H), 1.11 (d, J=6.2 Hz, 3H).

Step 3) 1-(5-amino-1H-benzo[d]imidazol-1-yl)propan-2-ol

To a solution of 1-(5-nitro-1H-benzo[d]imidazol-1-yl)propan-2-ol (310mg, 1.4014 mmol) in MeOH (20 mL) was added Pd/C (10%, 500 mg). Thereaction mixture was stirred at rt under a H₂ atmosphere for 8 h andfiltered through a Celite pad. The filter cake was washed with MeOH (50ml), and the filtrate was concentrated in vacuo. The residue waspurified by a flash column chromatography (7 M) NH₃ in MeOH/DCM(v/v)=1/20) to give the title compound as a white solid (130 mg, 48.5%).

MS (ESI, pos.ion) m/z: 192.3 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (s, 1H), 7.23 (d, J=8.5 Hz, 1H), 6.76(d, J=1.6 Hz, 1H), 6.58 (dd, J=8.5, 1.7 Hz, 1H), 4.94 (d, J=4.4 Hz, 1H),4.69 (s, 2H), 4.08-4.02 (m, 1H), 3.98-3.91 (m, 2H), 1.05 (d, J=5.6 Hz,3H).

Step 4)6-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(206.0 mg, 0.59 mmol) and1-(5-amino-1H-benzo[d]imidazol-1-yl)propan-2-ol (130 mg, 0.68 mmol) in1,4-dioxane (10 mL) were added Pd(OAc)₂ (13.4 mg, 0.060 mmol), BINAP(33.6 mg, 0.054 mmol) and Cs₂CO₃ (371.5 mg, 1.14 mmol). The reactionmixture was stirred at reflux for 4 h and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as a white solid (176 mg, 59.2%).

MS (ESI, pos.ion) m/z: 504.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 504.2030 [M+H]⁺; calculated value forC₂₅H₂₇ClN₉O [M+H]⁺ is 504.2027.

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.18 (s, 1H), 8.50 (d, J=2.1 Hz, 1H),8.21 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.85 (dd, J=9.1, 2.0 Hz, 1H),7.48-7.42 (m, 2H), 7.01 (d, J=9.1 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 4.96(d, J=4.7 Hz, 1H), 4.55 (d, J=12.5 Hz, 2H), 4.39-4.31 (m, 1H), 4.17-4.09(m, 1H), 4.05-3.93 (m, 2H), 3.11 (t, J=12.5 Hz, 2H), 2.00 (d, J=11.2 Hz,2H), 1.65-1.55 (m, 2H), 1.07 (d, J=5.9 Hz, 3H).

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 158.9, 158.2, 156.7, 153.4, 152.6,144.6, 143.5, 139.9, 135.2, 129.7, 118.7, 115.6, 109.9, 109.1, 106.4,102.7, 94.7, 65.0, 51.4, 48.3, 43.8, 30.6, 20.9.

Example 626-(4-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 1-((2-amino-4-nitrophenyl)amino)-2-methylpropan-2-ol

To a solution of 2-fluoro-5-nitroaniline (500 mg, 3.20 mmol) and1-amino-2-methylpropan-2-ol (342 mg, 3.84 mmol) in DMSO (6 mL) was addedpotassium carbonate (660 mg, 4.78 mmol). The reaction mixture wasstirred at 100° C. overnight, then cooled down to rt and quenched withwater (50 mL). The resulted mixture was extracted with EtOAc (100 mL×3).The combined organic phases were washed with brine (100 mL×2), driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc/PE (v/v)=1/2) togive the title compound as a red solid (600 mg, yield 83.2%).

MS (ESI, pos. ion) m/z: 226.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 7.51 (dd, J=8.9, 2.5 Hz, 1H), 7.43(d, J=2.6 Hz, 1H), 6.57 (d, J=9.0 Hz, 1H), 5.55 (t, J=5.4 Hz, 1H), 5.18(s, 2H), 4.59 (s, 1H), 3.13 (d, J=5.6 Hz, 2H), 1.18 (s, 6H).

Step 2) 2-methyl-1-(5-nitro-1H-benzo[d][1,2,3]triazol-1-yl)propan-2-ol

To a solution of 1-((2-amino-4-nitrophenyl)amino)-2-methylpropan-2-ol(350 mg, 1.55 mmol) in AcOH (2 mL) was added a sodium nitrite aqueoussolution (2 M, 2 mL, 4 mmol). The reaction mixture was stirred at rtovernight and adjusted to pH=10 with a saturated NaHCO₃ aqueoussolution, then extracted with DCM (100 mL×3). The combined organicphases were dried over anhydrous Na₂SO₄ and concentrated in vacuo togive the title compound as a yellow solid (360 mg, yield 98.1%).

MS (ESI, pos. ion) m/z: 237.0 [M+H]⁺;

Step 3) 1-(5-amino-1H-benzo[d][1,2,3]triazol-1-yl)-2-methylpropan-2-ol

To a solution of2-methyl-1-(5-nitro-1H-benzo[d][1,2,3]triazol-1-yl)propan-2-ol (360 mg,1.52 mmol) in EtOH (10 mL) was added Pd/C (10%, 100 mg). The mixture wasplaced in a high pressure autoclave under 2 MPa Hz, and stirred at rtfor 3 h, then filtered through a celite pad. The filtrate wasconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as abrown solid (300 mg, yield 95.4%).

MS (ESI, pos. ion) m/z: 207.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 7.53 (d, J=9.3 Hz, 1H), 6.990-6.88(m, 2H), 5.15 (s, 2H), 4.77 (s, 1H), 4.44 (s, 2H), 1.12 (s, 6H).

Step 4)6-(4-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(103 mg, 0.294 mmol) and1-(5-amino-1H-benzo[d][1,2,3]triazol-1-yl)-2-methylpropan-2-ol (90 mg,0.436 mmol) in 1,4-dioxane (15 mL) were added Pd(OAc)₂ (6 mg, 0.026mmol), BINAP (17 mg, 0.027 mmol) and Cs₂CO₃ (186 mg, 0.570 mmol). Thereaction mixture was stirred at 100° C. for 3 h and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/30) to give the title compound as a white solid (90mg, yield 58.8%).

MS (ESI, pos. ion) m/z: 520.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 520.2101 [M+H]⁺; calculated value forC₂₄H₂₇ClN₁₁O [M+H]⁺ is 520.2089;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.49 (s, 1H), 8.60 (s, 1H), 8.01 (s,1H), 7.88 (d, J=9.7 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.65 (d, J=8.8 Hz,1H), 7.45 (d, J=9.7 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 4.82 (s, 1H), 4.67(d, J=12.2 Hz, 2H), 4.54 (s, 2H), 4.46-4.32 (m, 1H), 3.23 (t, J=12.5 Hz,2H), 2.08 (d, J=10.9 Hz, 2H), 1.73-1.65 (m, 2H), 1.14 (s, 6H).

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 158.6, 158.1, 156.8, 153.5, 145.7,137.0, 131.1, 129.9, 128.4, 121.4, 117.5, 111.6, 111.2, 105.3, 103.6,70.0, 58.3, 48.3, 43.9, 30.6, 27.3.

Example 636-(4-((5-chloro-2-((1-(cyclopropylmethyl)-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 1-(cyclopropylmethyl)-5-nitro-1H-benzo[d]imidazole

To a solution of 2-fluoro-5-nitroaniline (998.3 mg, 6.4 mmol) in DMSO(20 mL) was added cyclopropylmethanamine (1.1 mL, 13 mmol). The reactionmixture was stirred at 120° C. overnight, cooled down to rt andtrimethoxymethane (2.5 mL, 32.1 mmol) was added. The resulted mixturewas stirred at 100° C. overnight, diluted with EtOAc (100 mL), andwashed with water (50 mL×3). The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (EtOAc/PE (v/v)=1/5) to give the title compound as ayellow solid (1.03 g, 74% for 2 steps).

MS (ESI, pos. ion) m/z: 218.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.70 (d, J=1.7 Hz, 1H), 8.22 (dd,J=9.0, 1.9 Hz, 1H), 8.20 (s, 1H), 7.48 (d, J=8.9 Hz, 1H), 4.07 (d, J=7.0Hz, 2H), 1.39-1.26 (m, 1H), 0.76 (q, J=5.6 Hz, 2H), 0.46 (q, J=5.2 Hz,2H).

Step 2) 1-(cyclopropylmethyl)-1H-benzo[d]imidazol-5-amine

To a solution of 1-(cyclopropylmethyl)-5-nitro-1H-benzo[d]imidazole(201.3 mg, 0.9 mmol) in EtOH (15 mL) was added palladium 10% on carbon(99.6 mg). The reaction mixture was stirred under a H₂ atmosphereovernight and filtered through a celite pad. The filtrate wasconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as apink solid (173.5 mg, 100%).

MS (ESI, pos. ion) m/z: 188.2 [M+H]⁺.

Step 3)6-(4-((5-chloro-2-((1-(cyclopropylmethyl)-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(150.1 mg, 0.4 mmol) and1-(cyclopropylmethyl)-1H-benzo[d]imidazol-5-amine (173.5 mg, 0.9 mmol)in 1,4-dioxane (5 mL) was were added Pd(OAc)₂ (8.8 mg, 0.04 mmol), BINAP(26.4 mg, 0.04 mmol) and Cs₂CO₃ (275.1 mg, 0.8 mmol). The reactionmixture was stirred at 100° C. for 4 h under N₂ atmosphere andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/30) to give the title compound as apink solid (189.3 mg, 88%).

MS (ESI, pos. ion) m/z: 501.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 501.2038 [M+H]⁺, calculated value forC₂₅H₂₆ClN₁₀ [M+H]⁺ is 501.2030;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.22 (s, 1H), 8.24 (s, 1H), 8.16 (s,1H), 7.96 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.58-7.38 (m, 3H), 6.90 (d,J=7.7 Hz, 1H), 4.66 (d, J=12.0 Hz, 2H), 4.50-4.24 (m, 1H), 4.06 (d,J=7.1 Hz, 2H), 3.24 (t, J=25.4, 12.9 Hz, 2H), 2.07 (d, J=10.8 Hz, 2H)1.81-1.50 (m, 2H), 1.26-1.21 (m, 1H), 0.65-0.47 (m, 2H), 0.43-0.26 (m,2H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 158.6, 158.2, 156.7, 153.4, 143.7,135.3, 131.0, 129.3, 128.3, 117.4, 115.8, 111.1, 109.7, 109.2, 102.8,48.4, 48.1, 43.8, 30.5, 11.3, 3.8.

Example 646-(4-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 2-methyl-1-(5-nitro-1H-benzo[d]imidazol-1-yl)propan-2-ol

To a solution of 2-fluoro-5-nitroaniline (305.0 mg, 2.0 mmol) in DMSO (3mL) was added 1-amino-2-methylpropan-2-ol (271.0 mg, 3.0 mmol). Thereaction mixture was stirred at 120° C. overnight, cooled down to rt andtrimethoxymethane (1.1 mL, 10.0 mmol) was added. The reaction mixturewas stirred at 100° C. overnight, diluted with EtOAc (100 mL), andwashed with water (50 mL×3). The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (EtOAc/PE (v/v)=2/1) to give the title compound as ayellow solid (435.7 mg, 95% for 2 steps).

MS (ESI, pos. ion) m/z: 236.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.55 (d, J=1.9 Hz, 1H), 8.18 (dd,J=9.0, 2.0 Hz, 1H), 8.10 (s, 1H), 7.51 (d, J=9.0 Hz, 1H), 4.17 (s, 2H),1.33 (s, 6H).

Step 2) 1-(5-amino-1H-benzo[d]imidazol-1-yl)-2-methylpropan-2-ol

To a solution of2-methyl-1-(5-nitro-1H-benzo[d]imidazol-1-yl)propan-2-ol (424.3 mg, 1.8mmol) in EtOH (25 mL) was added palladium 10% on carbon (99.6 mg). Thereaction mixture was stirred under a H₂ atmosphere overnight andfiltered through a Celite pad. The filtration was concentrated in vacuo.The residue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as an orange red solid (251.8 mg,68%).

MS (ESI, pos. ion) m/z: 206.0 [M+H]⁺.

Step 3)6-(4-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(139.6 mg, 0.4 mmol) and2-methyl-1-(5-nitro-1H-benzo[a]imidazol-1-yl)propan-2-ol (110.1 mg, 0.5mmol) in 1,4-dioxane (5 mL) were added Pd(OAc)₂ (9.2 mg, 0.04 mmol),BINAP (25.1 mg, 0.04 mmol) and Cs₂CO₃ (263.0 mg, 0.8 mmol). The reactionmixture was stirred at 100° C. for 4 h under N₂ atmosphere andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/30) to give the title compound as awhite solid (86.7 mg, 42%).

MS (ESI, pos. ion) m/z: 518.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 518.2190 [M+H]⁺, calculated value forC₂₆H₂₉ClN₉O [M+H]⁺ is 501.2184;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.17 (s, 1H), 8.51 (d, J=2.0 Hz, 1H),8.20 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.85 (dd, J=9.1, 2.2 Hz, 1H),7.50 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 1.3 Hz, 1H), 7.01 (d, J=9.1 Hz,1H), 6.87 (d, J=7.8 Hz, 1H), 4.76 (s, 1H), 4.56 (d, J=12.9 Hz, 2H),4.40-4.27 (m, 1H), 4.09 (s, 2H), 3.11 (t, J=12.5 Hz, 2H), 2.01 (d,J=10.7 Hz, 2H), 1.65-1.56 (m, 2H), 1.10 (s, 6H);

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 159.4, 158.7, 157.2, 153.9, 153.1,145.6, 143.6, 140.5, 135.5, 130.8, 119.3, 116.2, 111.0, 109.4, 106.9,95.2, 70.1, 55.1, 44.3, 31.1, 27.7.

Example 656-(4-((5-chloro-2-((1-propyl-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 4-nitro-N¹-propylbenzene-1,2-diamine

To a solution of 2-fluoro-5-nitroaniline (1.00 g, 6.44 mmol) and K₂CO₃(1.76 g, 12.72 mmol) in DMSO (10 mL) was added propan-1-amine (0.8 mL,10 mmol). The reaction mixture was stirred at 80° C. overnight andconcentrated in vacuo. The residue was added water (40 mL) and extractedwith EtOAc (400 mL). The organic phase was washed with water (10 mL×3),dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was apurified by flash column chromatography (EtOAc/PE (v/v)=1/4) to give thetitle compound as a red solid (1.02 g, 81.4%).

MS (ESI, pos. ion) m/z: 196.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.83 (dd, J=8.9, 2.4 Hz, 1H), 7.62 (d,J=2.4 Hz, 1H), 6.54 (d, J=8.9 Hz, 1H), 4.32 (s, 1H), 3.34 (s, 2H), 3.19(s, 2H), 1.78-1.67 (m, 2H), 1.04 (t, J=7.4 Hz, 3H).

Step 2) 5-nitro-1-propyl-1H-benzo[d][1,2,3]triazole

To a solution of 4-nitro-NI-propylbenzene-1,2-diamine (1.02 g, 5.24mmol) in acetic acid (20 mL) was added a solution of NaNO₂ in water (5.2mL, 10.4 mmol). The reaction mixture was stirred at rt overnight andconcentrated in vacuo. The residue was adjusted to pH=8 with a saturatedNa₂CO₃ aqueous solution and extracted with EtOAc (150 mL×2). Thecombined organic phases were washed with brine (5 mL×2), dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bya flash column chromatography (EtOAc/PE (v/v)=1/10) to give the titlecompound as red oil (773.0 mg, 71.6%).

MS (ESI, pos. ion) m/z: 207.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.99 (d, J=1.7 Hz, 1H), 8.38 (dd,J=9.1, 1.9 Hz, 1H), 7.65 (d, J=9.1 Hz, 1H), 4.67 (t, J=7.1 Hz, 2H),2.13-2.02 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).

Step 3)1-propyl-1H-benzo[d][1,2,3]triazol-5-amine

To a solution of 5-nitro-1-propyl-1H-benzo[d][1,2,3]triazole (773.0 mg,3.75 mmol) in MeOH (10 mL) was added Pd/C (151.8 mg, 10%). The reactionmixture was stirred at rt in a high pressure autoclave under 2 MPa H₂overnight and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by a flash column chromatography (MeOH/DCM(v/v)=1/15) to give the title compound as a red solid (409.4 mg, 62.0%).

MS (ESI, pos. ion) m/z: 177.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.31 (d, J=8.7 Hz, 1H), 7.19 (d, J=1.5Hz, 1H), 6.92 (dd, J=8.7, 1.9 Hz, 1H), 4.51 (t, J=7.1 Hz, 2H), 3.82 (s,2H), 2.05-1.96 (m, 2H), 0.95 (t, J=7.4 Hz, 3H).

Step 4)6-(4-((5-chloro-2-((1-propyl-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(783.2 mg, 2.24 mmol) and 1-propyl-1H-benzo[d][1,2,3]triazol-5-amine(395.2 mg, 2.24 mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)₂ (51.5mg, 0.23 mmol), BINAP (140.3 mg, 0.22 mmol) and Cs₂CO₃ (1.47 g, 4.52mmol). The reaction mixture was stirred at 100° C. for 2 h andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM=1/20) to give the title compound as a beigesolid (232.4 mg, yield 21.2%).

MS (ESI, pos. ion) m/z: 490.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 490.1982 [M+H]⁺; calculated value forC₂₃H₂₅ClN₁₁ [M+H]⁺ is 490.1983;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.52 (s, 1H), 8.62 (s, 1H), 8.01 (s,1H), 7.88 (d, J=9.7 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 7.70 (d, J=9.0 Hz,1H), 7.45 (d, J=9.7 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 4.67 (d, J=12.1 Hz,2H), 4.60 (t, J=6.8 Hz, 2H), 4.46-4.34 (m, 1H), 3.22 (t, J=12.5 Hz, 2H),2.08 (d, J=8.5 Hz, 2H), 1.96-1.87 (m, 2H), 1.73-1.64 (m, 2H), 0.85 (t,J=7.3 Hz, 3H);

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 158.6, 158.0, 156.8, 153.5, 145.9,137.3, 131.1, 128.7, 128.4, 121.6, 117.5, 111.2, 110.1, 105.5, 103.6,49.0, 48.3, 43.9, 30.5, 22.7, 11.0.

Example 666-(4-((5-chloro-2-((3-(2-hydroxypropan-2-yl]imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(100 mg, 0.286 mmol) and2-(7-aminoimidazo[1,2-a]pyridin-3-yl)propan-2-ol (110 mg, 0.575 mmol) in1,4-dioxane (20 mL) were added Pd(OAc)₂ (6 mg, 0.026 mmol), BINAP (17mg, 0.027 mmol) and Cs₂CO₃ (186 mg, 0.570 mmol). The reaction mixturewas stirred at 100° C. for 2 h under N₂ atmosphere and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/40) to give the title compound as a white solid (60mg, 41.6%).

MS (ESI, pos. ion) m/z: 505.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 505.1986 [M+H]⁺; calculated value forC₂₄H₂₆ClN₁₀O [M+H]⁺ is 505.1980;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.65 (s, 1H), 8.58 (d, J=7.5 Hz, 1H),8.25 (s, 1H), 8.05 (s, 1H), 7.87 (d, J=9.7 Hz, 1H), 7.44 (d, J=9.7 Hz,1H), 7.25 (s, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.9 Hz, 1H), 5.32(s, 1H), 4.64 (d, J=12.4 Hz, 2H), 4.48-4.32 (m, 1H), 3.24 (t, J=12.5 Hz,2H), 2.07 (d, J=11.6 Hz, 2H), 1.73-1.63 (m, 2H), 1.59 (s, 6H);

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 174.4, 158.6, 157.6, 156.9, 153.4,145.8, 131.1, 130.0, 129.7, 128.4, 126.9, 117.5, 111.2, 107.6, 104.6,66.9, 48.3, 43.8, 30.5, 29.1.

Example 676-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) tert-butyl (mesitylsulfonyl)oxycarbamate

To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (9.91 g,45.3 mmol) and tert-butyl hydroxycarbamate (6.10 g, 45.8 mmol) in EtOAc(60 mL) was added triethylamine (7.8 mL, 56 mmol) dropwise at −10° C.After addition, the reaction mixture was warmed up to 0° C. and stirredfor 2 h, quenched with water (30 mL) and separated. The separatedorganic layer was washed with water (30 mL×2), concentrated in vacuo,and the residue was used to the next step without further purification.

MS (ESI, pos. ion) m/z: 338.1 [M+Na]⁺.

Step 2) O-(mesitylsulfonyl)hydroxylamine

To a solution of tert-butyl (mesitylsulfonyl)oxycarbamate (14.30 g, 45.3mmol) in EtOAc (60 mL) was added concentrated sulfuric acid (4.5 mL,83.0 mmol) dropwise. After addition, the reaction mixture was stirred at0° C. overnight, neutralized by a saturated sodium carbonate aqueoussolution and separated. The separated organic layer was washed withwater (60 mL×3), concentrated in vacuo, and the residue was used to thenext step without further purification.

Step 3) 1,2-diamino-5-bromopyridin-1-ium 2,4,6-trimethylbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (9.75 g, 45.3 mmol) inEtOAc (60 mL) was added 5-bromopyridin-2-amine (4.05 g, 23.4 mmol) at 5°C. The reaction mixture was stirred for 1 h and filtered. The filtercake was washed with EtOAc (15 mL×3) to give the title compound as awhite solid (5.25 g, 58% for 3 steps).

MS (ESI, pos. ion) m/z: 188.1 [M₁]⁺;

MS (ESI, neg. ion) m/z: 199.1 [M₂]⁻.

Step 4) ethyl 3-hydroxy-3-methylbutanoate

To a solution of LiHMDS (1 mol/L in THF, 20 mL, 20 mmol) was added EtOAc(2 mL, 20.5 mmol) dropwise at −78° C. After addition, the reactionmixture was stirred for 1 h and acetone (1.8 mL, 24 mmol) was addeddropwise. After addition, the reaction mixture was continued to stir for0.5 h, quenched with a HCl aqueous solution (2 M, 15 mL, 30 mmol) andextracted with EtOAc (30 mL×2). The combined organic phases were washedwith a saturate NaHCO3 aqueous solution (15 mL), dried over Na₂SO₄ andconcentrated in vacuo to give the title compound as yellow oil (2.99 g,100%).

¹H NMR (400 MHz, CDCl₃): δ (ppm) 4.18-4.04 (m, 2H), 3.66 (s, 1H), 2.43(s, 2H), 1.27-1.14 (m, 9H).

Step 5)1-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of 1,2-diamino-5-bromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (2.01 g, 5.2 mmol) in methnoal (20 mL)were added ethyl 3-hydroxy-3-methylbutanoate (1.50 g, 10.3 mmol) andNaOH (212.3 mg, 5.3 mmol). The reaction mixture was stirred at 70° C.overnight and concentrated in vacuo. The residue was purified by asilica gel column chromatography (EtOAc/PE (v/v)=1/1) to give the titlecompound as a white solid (719.0 mg, 51%).

MS (ESI, pos. ion) m/z: 270.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.67 (s, 1H), 7.57 (s, 2H), 4.10 (s,1H), 3.06 (s, 2H), 1.27 (s, 6H).

Step 6)1-(6-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of1-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol(400.1 mg, 1.5 mmol) and diphenylmethanimine (352.1 mg, 1.9 mmol) in1,4-dioxane (10 mL) were added Pd2(dba)₃ (136.0 mg, 0.15 mmol), BINAP(92.3 mg, 0.15 mmol) and Cs₂CO₃ (963.5 mg, 3.0 mmol). The reactionmixture was stirred at 100° C. under N₂ atmosphere overnight andconcentrated in vacuo. The residue was dissolved in DCM (100 mL) andwashed with water (30 mL×2). The organic phase was concentrated in vacuoto give the title compound as brown oil, which was used to the next stepwithout further purification.

MS (ESI, pos. ion) m/z: 371.2 [M+H]⁺.

Step 7)1-(6-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of1-(6-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol(548.6 mg, 1.5 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc(3M, 2.5 mL, 7.5 mmol). The reaction mixture was stirred at rt for 1 hand concentrated in vacuo. The residue was neutralized to pH=9 with asolution of NaOH (1M) and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as a yellow solid (288.2 mg, 94% for 2 steps).

MS (ESI, pos. ion) m/z: 207.2 [M+H]⁺.

Step 8)6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(148.6 mg, 0.4 mmol) and1-(6-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol(117.0 mg, 0.6 mmol) in 1,4-dioxane (4 mL) were added Pd(OAc)₂ (10.3 mg,0.04 mmol), BINAP (26.3 mg, 0.04 mmol) and Cs₂CO₃ (280.4 mg, 0.9 mmol).The reaction mixture was stirred at 100° C. overnight under N₂atmosphere and concentrated in vacuo. The residue was purified by asilica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the titlecompound as a creamy white solid (182.4 mg, 83%).

MS (ESI, pos. ion) m/z: 519.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.2141 [M+H]⁺; calculated value forC₂₅H₂₈ClN₁₀O [M+H]⁺ is 519.2136;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.60 (s, 1H), 9.56 (s, 1H), 8.51 (d,J=1.7 Hz, 1H), 8.03 (s, 1H), 7.86 (dd, J=9.0, 2.0 Hz, 1H), 7.71-7.65 (m,2H), 7.09 (d, J=7.6 Hz, 1H), 6.99 (d, J=9.1 Hz, 1H), 4.560-4.54 (m, 3H),4.40-4.26 (m, 1H), 3.11 (t, J=12.4 Hz, 2H), 2.86 (s, 2H), 2.01 (d,J=10.7 Hz, 2H), 1.70-1.56 (m, 2H), 1.14 (s, 6H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 164.1, 159.5, 158.0, 157.3, 153.8,153.0, 146.9, 140.4, 129.9, 125.7, 119.2, 116.9, 115.1, 106.9, 95.3,69.7, 55.3, 44.3, 43.1, 31.0, 29.7.

Example 686-(4-((5-chloro-2-((3-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate

To a solution of ethyl 2-chloroacetate (10.0 g, 81.6 mmol) and ethylformate (6.65 g, 89.8 mmol) in THF (100 mL) was added potassiumt-butoxide (1 M, 90 mL, 90 mmol) slowly at 0° C. under N₂ atmosphere.After addition, the reaction mixture was warmed up to rt and stirred for24 h, then filtered. The filter cake was washed with THF (50 mL) anddried under vacuum to give the title compound as a yellow solid (13.0 g,84.5%).

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.90 (s, 1H), 3.96-3.91 (m 2H), 1.12(t, J=7.0 Hz, 3H).

Step 2) ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate

To a solution of potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate(13.0 g, 68.9 mmol) and 4-bromopyridin-2-amine (3.00 g, 17.3 mmol) inethanol (60 mL) was added conc. H₂SO₄ (2 mL). The reaction mixture wasstirred at 90° C. for 18 h and concentrated in vacuo. The residue wasadjusted to pH=10 with a saturated NaHCO₃ aqueous solution, andextracted with EtOAc (200 mL×3). The combined organic phases were washedwith brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated invacuo. The residue was purified by a silica gel column chromatography(EtOAc/PE (v/v)=1/4) to give the title compound as a white solid (4.6 g,99%).

MS (ESI, pos. ion) m/z: 269.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 9.17 (d, J=7.3 Hz, 1H), 8.26 (s, 1H),7.92 (d, J=1.1 Hz, 1H), 7.14 (dd, J=7.3, 1.6 Hz, 1H), 4.41 (q, J=7.1 Hz,2H), 1.42 (t, J=7.1 Hz, 3H).

Step 3) 2-(7-bromoimidazo[1,2-a]pyridin-3-yl)propan-2-ol

To a solution of ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate(830.0 mg, 3.07 mmol) in THF (20 mL) was added a solution ofmethylmagnesium bromide (3 M in THF, 13 mL, 39 mmol) dropwise under N₂atmosphere at −78° C. After addition, the reaction mixture was warmed upto 0° C., stirred overnight and quenched with water (5 mL), thenconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (EtOAc/PE (v/v)=1/1) to give the title compound as ayellow solid (900 mg, 47.5%).

MS (ESI, pos. ion) m/z: 255.0 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.55 (d, J=7.4 Hz, 1H), 7.71 (d, J=1.2Hz, 1H), 7.31 (s, 1H), 6.88 (dd, J=7.4, 1.8 Hz, 1H), 1.74 (s, 6H).

Step 4)2-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-3-yl)propan-2-ol

To a solution of 2-(7-bromoimidazo[1,2-a]pyridin-3-yl)propan-2-ol (1.70g, 6.70 mmol) and diphenylmethanimine (1.41 g, 7.78 mmol) in 1,4-dioxane(50 mL) were added Pd₂(dba)₃ (610 mg, 0.666 mmol), BINAP (410 mg, 0.658mmol) and Cs₂CO₃ (4.31 g, 13.2 mmol). The reaction mixture was stirredat 100° C. overnight under N₂ atmosphere and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (EtOAc/PE(v/v)=1/1) to give the title compound as a yellow solid (1.70 g, 72.0%).

MS (ESI, pos. ion) m/z: 356.1 [M+H]⁺.

Step 5) 2-(7-aminoimidazo[1,2-a]pyridin-3-yl)propan-2-ol

To a solution of2-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-3-yl)propan-2-ol(900 mg, 2.53 mmol) in 1,4-dioxane (20 mL) was added a solution of HClin water (4 M, 7 mL, 28 mmol). The reaction mixture was stirred at rtfor 1 h and concentrated in vacuo. The residue was adjusted to pH=8 witha saturated NaHCO₃ aqueous solution and concentrated in vacuo. Theresidue was purified by a silica gel chromatography ((MeOH (7M NH₃)/DCM(v/v)=1/1) to give the title compound as a brown solid (280 mg, 57.8%)

MS (ESI, pos. ion) m/z: 192.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.35 (d, J=7.3 Hz, 1H), 6.94 (s, 1H),6.36 (dd, J=7.5, 1.8 Hz, 1H), 6.32 (s, 1H), 5.52 (s, 2H), 4.46 (s, 1H),1.54 (s, 6H).

Step 6)6-(4-((5-chloro-2-((3-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(80 mg, 0.229 mmol) and 2-(7-aminoimidazo[1,2-a]pyridin-3-yl)propan-2-ol(92 mg, 0.481 mmol) in 1,4-dioxane (10 mL) were added Pd(OAc)₂ (5 mg,0.022 mmol), BINAP (14 mg, 0.022 mmol) and Cs₂CO₃ (150 mg, 0.460 mmol).The reaction mixture was stirred at 100° C. for 2 h and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/30) to give the title compound as a white solid (70mg, 60.6%).

MS (ESI, pos. ion) m/z: 504.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 504.2061 [M+H]⁺; calculated value forC₂₅H₂₇ClN₉O [M+H]⁺ is 504.2027;

¹H NMR (600 MHz, DMSO-d₆): δ (ppm) 9.59 (s, 1H), 8.55 (d, J=7.5 Hz, 1H),8.50 (d, J=2.0 Hz, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.85 (dd, J=9.1, 2.1Hz, 1H), 7.20 (s, 1H), 7.09-7.04 (m, 2H), 7.00 (d, J=9.1 Hz, 1H), 5.31(s, 1H), 4.55 (d, J=11.9 Hz, 2H), 4.39-4.32 (m, 1H), 3.15 (t, J=12.6 Hz,2H), 2.02 (d, J=11.5 Hz, 2H), 1.66-1.60 (m, 2H), 1.58 (s, 6H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 158.9, 157.7, 156.8, 153.3, 152.6,146.3, 139.4, 137.1, 129.7, 128.2, 126.5, 118.8, 107.1, 106.4, 104.3,100.7, 94.8, 66.9, 48.5, 43.8, 30.5, 29.1.

Example 696-(4-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(100 mg, 0.286 mmol) and1-(5-amino-1H-benzo[d][1,2,3]triazol-1-yl)-2-methylpropan-2-ol (90 mg,0.436 mmol) in 1,4-dioxane (6 mL) were added Pd(OAc)₂ (6 mg, 0.026mmol), BINAP (17 mg, 0.027 mmol) and Cs₂CO₃ (186 mg, 0.570 mmol). Thereaction mixture was stirred at 100° C. for 3 h and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/30) to give the title compound as a white solid (80mg, yield 53.8%).

MS (ESI, pos. ion) m/z: 519.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.2140 [M+H]⁺; calculated value forC₂₅H₂₈ClN₁₀O [M+H]⁺ is 519.2136;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.48 (s, 1H), 8.59 (s, 1H), 8.50 (s,1H), 8.00 (s, 1H), 7.85 (dd, J=9.3, 1.6 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H),7.65 (d, J=8.9 Hz, 1H), 7.01 (d, J=9.2 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H),4.80 (s, 1H), 4.58 (d, J=12.8 Hz, 2H), 4.53 (s, 2H), 4.44-4.29 (m, 1H),3.12 (t, J=12.5 Hz, 2H), 2.03 (d, J=12.6 Hz, 2H), 1.67-1.58 (m, 2H),1.14 (s, 6H);

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 158.9, 158.1, 156.8, 153.5, 152.7,145.7, 140.0, 137.1, 129.9, 121.4, 118.8, 111.6, 106.5, 105.2, 103.5,94.8, 70.0, 58.3, 48.5, 43.9, 30.7, 27.3.

Example 706-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate

To a solution of 4-bromopyridin-2-amine (5.00 g, 28.9 mmol) in EtOH (50mL) was added ethyl 3-bromo-2-oxopropanoate (12.02 g, 61.6 mmol). Thereaction mixture was stirred at reflux for 8 h and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/10) to give the title compound as a pale yellow solid(7.02 g, 90%).

MS (ESI, pos, ion): 269.1 [M+H]⁺;

Step 2) ethyl7-((diphenylmethylene)amino)imidazo[1,2-a]pyridine-2-carboxylate

To a solution of ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate (8.0g, 30.0 mmol) and diphenylmethanimine (8.10 g, 45.0 mmol) in 1,4-dioxane(100 mL) were added Pd₂(dba)₃ (2.76 g, 3.0 mmol), BINAP (1.84 g, 3.0mmol) and Cs₂CO₃ (19.60 g, 60.3 mmol). The reaction mixture was stirredat reflux for 6 h under N₂ atmosphere, cooled down to rt and filtered.The filtrate was concentrated in vacuo. The residue was purified by asilica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the titlecompound as a pale yellow solid (5.20 g, 47%).

MS (ESI, pos, ion): 370.2 [M+H]⁺.

Step 3) ethyl 7-aminoimidazo[1,2-a]pyridine-2-carboxylate

To a solution of7-((diphenylmethylene)amino)imidazo[1,2-a]pyridine-2-carboxylate (5.03g, 13.6 mmol) in DCM (20 mL) was added a solution of HCl in EtOAc (3M,50 mL, 150 mmol). The reaction mixture was stirred at rt for 2 h andconcentrated in vacuo. The residue was neutralized to pH=9 with asolution of NaOH (1M) and extracted with EtOAc (100 mL×4). The combinedorganic phases were washed with brine (100 mL×3), dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/10) to give the title compound as apale yellow solid (2.10 g, 75%).

MS (ESI, pos, ion): 206.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.16 (d, J=7.4 Hz, 1H), 8.14 (s, 1H),6.47 (d, J=7.2 Hz, 1H), 6.33 (s, 1H), 5.84 (s, 2H), 4.24 (q, J=7.0 Hz,2H), 1.28 (t, J=7.1 Hz, 3H).

Step 4) 2-(7-aminoimidazo[1,2-a]pyridin-2-yl)propan-2-ol

To a solution of ethyl 7-aminoimidazo[1,2-a]pyridine-2-carboxylate (2.10g, 10.2 mmol) in THF (50 mL) was added methylmagnesium bromide (2.0 Msolution in THF, 55 mL, 110 mmol) dropwise at −78° C. under N₂atmosphere. After addition, the reaction mixture was warmed up to 0° C.and stirred for 5 h, then quenched with water (30 mL). the resultedmixture was extracted with EtOAc (60 mL×4). The combined organic phaseswere washed with brine (40 mL×3), dried over Na₂SO₄ and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/10) to give the title compound as a pale yellow solid(200.5 mg, 10%).

MS (ESI, pos, ion): 192.3 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.31 (d, J=7.3 Hz, 1H), 7.63 (s, 1H),7.04 (s, 2H), 6.75 (dd, J=7.3, 1.9 Hz, 1H), 6.55 (d, J=1.2 Hz, 1H), 1.51(s, 6H).

Step 5)6-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of 2-(7-aminoimidazo[1,2-a]pyridin-2-yl)propan-2-ol (90.0mg, 0.47 mmol) and6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(81.2 mg, 0.23 mmol) in dioxane (10 ml) were added Pd(OAc)₂ (23.4 mg,0.10 mmol), BINAP (60.1 mg, 0.10 mmol) and Cs₂CO₃ (312.0 mg, 0.96 mmol).The reaction mixture was stirred at reflux for 5 h, cooled down to rtand quenched with water (20 mL), then extracted with EtOAc (40 mL×4).The combined organic phases were washed with brine (40 mL×3), dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by a silicagel column chromatography (MeOH/DCM (v/v)=1/10) to give the titlecompound as a white solid (62.5 mg, 26%).

MS (ESI, pos, ion): 504.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 504.2024 [M+H]⁺; calculated value forC₂₅H₂₇ClN₉O [M+H]⁺ is 504.2027;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) δ 9.51 (s, 1H), 8.50 (s, 1H), 8.30(d, J=7.3 Hz, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.85 (dd, J=9.1, 1.8 Hz,1H), 7.49 (s, 1H), 7.08-7.02 (m, 2H), 7.00 (d, J=9.3 Hz, 1H), 4.84 (s,1H), 4.54 (d, J=13.5 Hz, 2H), 4.42-4.29 (m, 1H), 3.16 (t, J=12.5 Hz,2H), 2.01 (d, J=14.3 Hz, 2H), 1.67-1.57 (m, 2H), 1.42 (s, 6H).

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 174.8, 159.5, 158.2, 157.2, 153.7,153.1, 140.4, 130.1, 126.7, 119.3, 107.6, 107.0, 106.6, 95.2, 69.2,56.5, 44.3, 31.1, 31.0.

Example 716-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of 2-(7-aminoimidazo[1,2-a]pyridin-2-yl)propan-2-ol (45.0mg, 0.24 mmol) and6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(42.0 mg, 0.12 mmol) in dioxane (2 mL) were added Pd(OAc)₂ (10.4 mg,0.046 mmol), BINAP (29.2 mg, 0.047 mmol) and Cs₂CO₃ (160.2 mg, 0.49mmol). The reaction mixture was stirred at reflux for 5 h, cooled downto rt and quenched with water (20 mL), then extracted with EtOAc (30mL×4). The combined organic phases were washed with brine (30 mL×3),dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bya silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give thetitle compound as a white solid (36.8 mg, 31%).

MS (ESI, pos, ion): 505.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 505.1976 [M+H]⁺; calculated value forC₂₄H₂₆ClN₁₀O [M+H]⁺ is 505.1980;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.90 (s, 1H), 8.46 (d, J=5.3 Hz, 1H),8.24 (s, 1H), 8.07 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.66 (s, 1H), 7.43(d, J=9.7 Hz, 1H), 7.29 (s, 1H), 7.09 (d, J=7.6 Hz, 1H), 5.27 (s, 1H),4.59 (d, J=12.7 Hz, 2H), 4.50-4.34 (m, 1H), 3.37 (s, 2H), 2.04 (d,J=12.8 Hz, 2H), 1.71-1.63 (m, 2H), 1.47 (s, 6H);

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 174.9, 167.4, 159.1, 157.9, 157.4,153.6, 131.6, 131.2, 130.1, 123.0, 128.7, 118.0, 111.6, 68.4, 48.5,44.1, 30.8, 30.8.

Example 726-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 1-(7-aminoimidazo[1,2-b]pyridazin-2-yl)-2-methylpropan-2-ol

To a solution of pyridazine-3,5-diamine (500 mg, 4.54 mmol) in ethanol(20 mL) was added 1-bromo-4-hydroxy-4-methylpentan-2-one (1.75 g, 8.97mmol). The reaction mixture was stirred at 80° C. for 6 h andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as ayellow solid (520 mg, 55.5%).

MS (ESI, pos. ion) m/z: 207.3 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.41 (d, J=2.5 Hz, 1H), 7.91 (s, 1H),7.18 (s, 2H), 6.94 (d, J=2.3 Hz, 1H), 4.81 (s, 1H), 2.76 (s, 2H), 1.16(s, 6H).

Step 2)6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-b]pyridazin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(100 mg, 0.286 mmol) and1-(7-aminoimidazo[1,2-b]pyridazin-2-yl)-2-methylpropan-2-ol (90 mg,0.429 mmol) in 1,4-dioxane (10 mL) were added Pd(OAc)₂ (6 mg, 0.026mmol), BINAP (17 mg, 0.027 mmol) and Cs₂CO₃ (186 mg, 0.570 mmol). Thereaction mixture was stirred at 100° C. for 2 h under N₂ atmosphere andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/30) to give the title compound as awhite solid (60 mg, 40.4%).

MS (ESI, pos. ion) m/z: 519.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.2136 [M+H]⁺; calculated value forC₂₅H₂₈ClN₁₀O [M+H]⁺ is 519.2136;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm): 9.81 (s, 1H), 8.58 (d, J=2.4 Hz,1H), 8.50 (t, J=2.3 Hz, 2H), 8.06 (s, 1H), 7.85 (dd, J=9.1, 2.3 Hz, 1H),7.81 (s, 1H), 7.13 (d, J=7.8 Hz, 1H), 6.99 (d, J=9.1 Hz, 1H), 4.67 (s,1H), 4.55 (d, J=12.8 Hz, 2H), 4.37-4.28 (m, 1H), 3.09 (t, J=12.3 Hz,2H), 2.73 (s, 2H), 2.00 (d, J=10.4 Hz, 2H), 1.68-1.58 (m, 2H), 1.09 (s,6H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 159.4, 158.0, 157.3, 153.8, 153.0,144.5, 140.4, 139.0, 132.0, 119.2, 113.5, 107.3, 107.0, 105.4, 95.3,70.0, 49.0, 44.3, 42.9, 31.0, 29.8.

Example 736-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 1-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of 5-bromopyridin-2-amine (1.91 g, 11.0 mmol) in ethanol(20 mL) was added 1-bromo-4-hydroxy-4-methylpentan-2-one (2.17 g, 11.1mmol). The reaction mixture was stirred at reflux overnight andconcentrated in vacuo. The residue was added water (30 mL). The resultedmixture was adjusted to pH=8 with a saturated Na₂CO₃ aqueous solutionand extracted with DCM (100 mL×2). The combined organic phases werewashed with water (5 mL×2), dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by a flash column chromatography(EtOAc/PE (v/v)=1/10) to give the title compound as a yellow solid (1.44g, 48.1%).

MS (ESI, pos. ion) m/z: 269.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.22 (dd, J=1.7, 0.7 Hz, 1H), 7.43 (d,J=9.5 Hz, 1H), 7.37 (s, 1H), 7.22 (dd, J=9.5, 1.8 Hz, 1H), 4.54 (s, 1H),2.88 (s, 2H), 1.23 (s, 6H).

Step 2)1-(6-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of1-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol (1.44 g, 5.35mmol) and diphenylmethanimine (1.1 mL, 6.60 mmol) in 1,4-dioxane (20 mL)were added Pd₂(dba)₃ (473.6 mg, 0.52 mmol), BINAP (319.7 mg, 0.51 mmol)and Cs₂CO₃ (3.42 g, 10.50 mmol). The reaction mixture was stirred at100° C. 2 h, then filtered. The filtrate was concentrated in vacuo. Theresidue was purified by a flash column chromatography (EtOAc/PE(v/v)=1/10) to give the title compound as a red solid (717.4 mg, 36.3%).

MS (ESI, pos. ion) m/z: 369.8 [M+H]⁺.

Step 3) 1-(6-aminoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of1-(6-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol(700.0 mg, 1.89 mmol) in DCM (15 mL) was added a solution of HCl inEtOAc (3 M, 0.9 mL, 2.70 mmol). The reaction mixture was stirred at rtfor 1 h and concentrated in vacuo. The residue was added water (30 mL).The resulted mixture was adjusted to pH=8 with a saturated Na₂CO₃aqueous solution and extracted with DCM (200 mL×3). The combined organicphases were dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by a flash column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as a black solid (94.5 mg,24.3%).

MS (ESI, pos. ion) m/z: 206.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.53 (d, J=1.5 Hz, 1H), 7.36 (d, J=9.4Hz, 1H), 7.22 (s, 1H), 6.76 (dd, J=9.4, 2.1 Hz, 1H), 4.78 (s, 1H), 3.41(s, 2H), 2.83 (s, 2H), 1.22 (s, 6H).

Step 4)6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(117.8 mg, 0.34 mmol) and1-(6-aminoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol (94.0 mg, 0.46mmol) in 1,4-dioxane (15 mL) were added Pd(OAc)₂ (10.1 mg, 0.045 mmol),BINAP (23.1 mg, 0.037 mmol) and Cs₂CO₃ (220.0 mg, 0.68 mmol). Thereaction mixture was stirred at 100° C. for 1.5 h and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/20) to give the title compound as a beige solid (147.2mg, 84.2%).

MS (ESI, pos. ion) m/z: 518.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 518.2193 [M+H]⁺; calculated value forC₂₆H₂₉ClN₉O [M+H]⁺ is 518.2184;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.55 (s, 1H), 9.25 (s, 1H), 8.49 (d,J=2.1 Hz, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.85 (dd, J=9.1, 2.3 Hz, 1H),7.71-7.64 (m, 2H), 7.00 (d, J=3.6 Hz, 1H), 6.98 (d, J=4.9 Hz, 1H), 4.80(s, 1H), 4.51 (d, J=12.9 Hz, 2H), 4.40-4.31 (m, 1H), 3.05 (t, J=12.2 Hz,2H), 2.81 (s, 2H), 1.96 (d, J=10.7 Hz, 2H), 1.67-1.57 (m, 2H), 1.13 (s,6H);

¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) 158.9, 157.6, 156.9, 153.1, 152.6,140.0, 137.8, 130.0, 124.9, 118.8, 115.2, 113.2, 112.9, 106.5, 104.5,94.8, 69.1, 48.0, 43.8, 40.2, 30.5, 29.2.

Example 746-(4-((5-chloro-2-((3-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 3-hydroxy-3-methylbutanoic acid

To a solution of ethyl 3-hydroxy-3-methylbutanoate (1.56 g, 10.7 mmol)in water (20 mL) was added hydroxyl sodium (851.0 mg, 21.3 mmol). Thereaction mixture was stirred at rt overnight and neutralized byconcentrated hydrochloric acid to pH=5, then extracted with EtOAc (50mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo to give the title compound as yellow oil (1.17 g,93%).

Step 2) N′-(4-bromopyridin-2-yl)-3-hydroxy-3-methylbutanehydrazide

To a solution of 3-hydroxy-3-methylbutanoic acid (1.17 g, 9.9 mmol) and4-bromo-2-hydrazinylpyridine (1.44 g, 7.7 mmol) in THF (20 mL) wereadded triethylamine (2.8 mL, 20.0 mmol) and HATU (4.62 g, 12.2 mmol).The reaction mixture was stirred at rt overnight and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/30) to give the title compound as a white solid (1.66g, 75%).

MS (ESI, pos. ion) m/z: 288.0 [M+H]⁺.

Step 3)1-(7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylpropan-2-ol

A mixture of N′-(4-bromopyridin-2-yl)-3-hydroxy-3-methylbutanehydrazide(1.66 g, 5.8 mmol) and acetic acid (10 mL) was stirred at 180° C. underthe microwave irradiation for 40 min, cooled down to rt and quenchedwith water (30 mL), then extracted with EtOAc (50 mL×3). The combinedorganic phases were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/30) to give the title compound as a white solid (330.4 mg, 21%).

MS (ESI, pos. ion) m/z: 270.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.47 (d, J=7.4 Hz, 1H), 8.06 (d,J=1.0 Hz, 1H), 7.07 (dd, J=7.4, 1.8 Hz, 1H), 4.69 (s, 1H), 3.19 (s, 2H),1.20 (s, 6H).

Step 4)1-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylpropan-2-ol

To a solution of1-(7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylpropan-2-ol(330.4 mg, 1.2 mmol) and diphenylmethanimine (445.0 mg, 2.5 mmol) in1,4-dioxane (5 mL) were added Pd₂(dba)₃ (112.0 mg, 0.12 mmol), BINAP(76.2 mg, 0.12 mmol) and Cs₂CO₃ (717.2 mg, 2.2 mmol). The reactionmixture was stirred at 100° C. under N₂ atmosphere overnight andconcentrated in vacuo. The residue was dissolved in DCM (100 mL) andwashed with water (30 mL×2). The organic phase was concentrated in vacuoto give the title compound as brown oil, which was used to the next stepwithout further purification.

MS (ESI, pos. ion) m/z: 371.3 [M+H]⁺.

Step 5)1-(7-amino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylpropan-2-ol

To a solution of1-(7-((diphenylmethylene)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylpropan-2-ol(453.0 mg, 1.2 mmol) in DCM (5 mL) was added a solution of HCl in EtOAc(3 M, 3 mL, 9 mmol). The reaction mixture was stirred at rt for 1 h andconcentrated in vacuo. The residue was neutralized to pH=9 with a NaOH(1M) aqueous solution and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as a yellow solid (252.2 mg, 100% for 2 steps).

MS (ESI, pos. ion) m/z: 207.2 [M+H]⁺.

Step 6)6-(4-((5-chloro-2-((3-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(50.0 mg, 0.14 mmol) and1-(7-amino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylpropan-2-ol(180.0 mg, 0.87 mmol) in 1,4-dioxane (3 mL) were added Pd(OAc)₂ (3.2 mg,0.014 mmol), BINAP (8.9 mg, 0.014 mmol) and K₂CO₃ (39.2 mg, 0.29 mmol).The reaction mixture was stirred overnight at 100° C. under N₂atmosphere and concentrated in vacuo. The residue was purified by asilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as a yellow solid (40.1 mg, 54%).

MS (ESI, pos. ion) m/z: 519.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.2146 [M+H]⁺; calculated value forC₂₅H₂₈ClN₁₀O [M+H]⁺ is 519.2136;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.75 (s, 1H), 8.50 (s, 1H), 8.33 (s,1H), 8.32 (d, J=7.5 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.15(d, J=7.6 Hz, 1H), 7.01 (t, J=7.4 Hz, 2H), 4.64 (s, 1H), 4.58 (d, J=12.7Hz, 2H), 4.42-4.29 (m, 1H), 3.21-3.06 (m, 4H), 2.03 (d, J=12.9 Hz, 2H),1.64 (m, 2H), 1.19 (s, 6H);

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 159.4, 158.1, 157.3, 153.8, 153.1,150.9, 144.5, 140.5, 139.4, 130.1, 124.9, 119.3, 109.2, 107.0, 96.4,95.3, 70.7, 49.2, 44.3, 38.1, 31.0, 29.8.

Example 756-(4-((5-chloro-2-((3-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(97.3 mg, 0.28 mmol) and1-(7-amino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylpropan-2-ol(121.3 mg, 0.59 mmol) in 1,4-dioxane (4 mL) were added Pd(OAc)₂ (7.2 mg,0.032 mmol), BINAP (18.8 mg, 0.030 mmol) and K₂CO₃ (79.5 mg, 0.58 mmol).The reaction mixture was stirred at 100° C. overnight under N₂atmosphere and concentrated in vacuo. The residue was purified by asilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as a white solid (139.4 mg, 96%).

MS (ESI, pos. ion) m/z: 520.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 520.2106 [M+H]⁺; calculated value forC₂₄H₂₇ClN₁₁O [M+H]⁺ is 520.2089;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.76 (s, 1H), 8.33 (s, 1H), 8.32 (d,J=7.7 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J=9.7 Hz, 1H), 7.45 (d, J=9.8 Hz,1H), 7.16 (d, J=7.7 Hz, 1H), 7.00 (dd, J=7.4, 1.1 Hz, 1H), 4.69-4.64 (m,3H), 4.46-4.33 (m, 1H), 3.26 (t, J=12.4 Hz, 2H), 3.11 (s, 2H), 2.08 (d,J=10.8 Hz, 2H), 1.77-1.62 (m, 2H), 1.19 (s, 6H);

¹³C NMR (150 MHz, DMSO-d₆): δ (ppm) 159.1, 158.1, 157.3, 153.9, 150.9,144.5, 139.4, 131.6, 128.8, 124.9, 117.9, 111.6, 109.2, 105.2, 96.5,70.7, 49.0, 44.4, 38.1, 30.9, 29.8.

Example 766-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

Step 1) 1-bromo-4-hydroxy-4-methylpentan-2-one

To a solution of 4-hydroxy-4-methyl-pentan-2-one (20.03 g, 172.4 mmol)in MeOH (120 mL) was added Br₂ (8.8 mL, 170 mmol) dropwise at 0° C.After addition, the reaction mixture was continued to stir for 3 h anddiluted with water (200 mL), then extracted with DCM (200 mL×3). Thecombined organic phases were dried over Na₂SO₄ and concentrated in vacuoto give the title compound as yellow oil (32.92 g, 97.9%).

¹H NMR (400 MHz, CDCl₃): δ (ppm) 3.91 (s, 2H), 2.83 (s, 2H), 1.29 (s,6H).

Step 2) 1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of 4-bromopyridin-2-amine (7.01 g, 40.5 mmol) in EtOH (150mL) was addedl-bromo-4-hydroxy-4-methyl-pentan-2-one (15.82 g, 81.1mmol). The reaction mixture was heated to reflux overnight andconcentrated in vacuo. The residue was adjusted to pH=8 with a saturatedNa₂CO₃ solution and extracted with DCM (150 mL×4). The combined organicphases were dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc/PE (v/v)=1/1) togive the title compound as a yellow solid (3.3 g, 30%).

MS (ESI, pos.ion) m/z: 269.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.93 (dd, J=7.1, 0.4 Hz, 1H), 7.71 (d,J=1.7 Hz, 1H), 7.37 (s, 1H), 6.87 (dd, J=7.1, 1.9 Hz, 1H), 4.57 (s, 1H),2.87 (s, 2H), 1.22 (s, 6H).

Step 3)1-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

To a solution of1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-2-methyl-propan-2-ol (3.3 g, 12.0mmol) and diphenylmethanimine (3.11 g, 17.2 mmol) in 1,4-dioxane (150mL) were added Pd₂(dba)₃ (1.03 g, 1.12 mmol), BINAP (746.5 mg, 1.20mmol) and Cs₂CO₃ (7.96 g, 24.4 mmol). The reaction mixture was stirredat reflux for 5 h under N₂ atmosphere and concentrated in vacuo. Theresidue was dissolved in DCM (20 mL) and dried over Na₂SO₄, thenfiltered. The filtrate was concentrated in vacuo to give the titlecompound as a brown semisolid, which was used to the next step withoutfurther purification.

MS (ESI, pos.ion) m/z: 370.2 [M+H]⁺.

Step 4) 1-(7-aminoimidazo[1,2-a]pyridin-2-yl)-2-methylpropan-2-ol

A mixture of1-[7-(benzhydrylideneamino)imidazo[1,2-a]pyridin-2-yl]-2-methyl-propan-2-ol(4.5 g, 12.0 mmol) and a solution of HCl in EtOAc (4 M, 80 mL, 320 mmol)was stirred at rt overnight and concentrated in vacuo. The residue wasadjusted to pH=8 with a saturated NaHCO₃ solution and concentrated invacuo. The residue was dissolved in DCM (200 mL) and dried over Na₂SO₄,then filtered, the filtrate was concentrated in vacuo. The residue waspurified by a silica gel column chromatography (7M NH₃ in MeOH/DCM(v/v)=1/30) to give the title compound as a yellow solid (1.84 g, 74%for 2 steps).

MS (ESI, pos.ion) m/z: 206.1 [M+H]⁺.

Step 5)6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(203.2 mg, 0.58 mmol) and1-(7-aminoimidazo[1,2-a]pyridin-2-yl)-2-methyl-propan-2-ol (139.5 mg,0.68 mmol) in 1,4-dioxane (10 mL) were added Pd(OAc)₂ (14.2 mg, 0.063mmol), BINAP (38.8 mg, 0.062 mmol) and Cs₂CO₃ (380.1 mg, 1.17 mmol). Thereaction mixture was stirred at reflux for 4 h under N₂ atmosphere andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/25) to give the title compound as apale yellow solid (93.9 mg, 31.2%)

MS (ESI, pos.ion) m/z: 518.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 518.2186 [M+H]⁺; calculated value forC₂₆H₂₉ClN₉O [M+H]⁺ is 518.2184;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.58 (s, 1H), 8.50 (d, J=2.1 Hz, 1H),8.30 (d, J=7.3 Hz, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.85 (dd, J=9.1, 2.3Hz, 1H), 7.49 (s, 1H), 7.07-7.02 (m, 2H), 7.00 (d, J=9.2 Hz, 1H), 4.97(s, 1H), 4.56 (d, J=12.8 Hz, 2H), 4.41-4.31 (m, 1H), 3.12 (t, J=12.5 Hz,2H), 2.68 (s, 2H), 2.01 (d, J=11.0 Hz, 2H), 1.67-1.57 (m, 2H), 1.07 (s,6H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 158.9, 157.6, 156.7, 153.3, 152.5,145.0, 143.5, 139.9, 137.6, 125.8, 118.7, 109.4, 107.0, 106.5, 104.2,100.1, 94.8, 69.6, 48.5, 43.8, 41.7, 30.5, 29.3.

Example 776-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 1,2,4-triaminopyridin-1-ium 2,4,6-trimethylbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (29.53 g, 137.2 mmol)in EtOAc (220 mL) was added pyridine-2,4-diamine (4.00 g, 36.7 mmol) at5° C. The reaction mixture was stirred 5° C. for 1 h and filtered. Thefilter cake was washed with EtOAc (10 mL×3) to give the title compoundas a yellow solid (6.90 g, 58%).

MS (ESI, pos. ion) m/z: 125.3 [M₁]⁺.

MS (ESI, neg. ion) m/z: 199.1 [M₂]⁻.

Step 2)1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl-2-methylpropan-2-ol

To a solution of 1,2,4-triaminopyridin-1-ium2,4,6-trimethylbenzenesulfonate (2.00 g, 6.2 mmol) in methnoal (20 mL)were added ethyl 3-hydroxy-3-methylbutanoate (3.60 g, 24.7 mmol) andNaOH (493.6 mg, 12.3 mmol). The reaction mixture was stirred at 70° C.overnight, then concentrated in vacuo. The residue was purified by asilica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the titlecompound as a yellow solid (183.2 mg, 14%).

MS (ESI, pos. ion) m/z: 207.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.35 (d, J=7.3 Hz, 1H), 6.45 (dd,J=7.3, 2.3 Hz, 1H), 6.41 (d, J=1.9 Hz, 1H), 6.08 (s, 2H), 4.69 (s, 1H),2.74 (s, 2H), 1.15 (s, 6H).

Step 3)6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(80.0 mg, 0.23 mmol) and1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol (70.3mg, 0.34 mmol) in 1,4-dioxane (3 mL) were added Pd(OAc)₂ (5.2 mg, 0.02mmol), BINAP (14.8 mg, 0.02 mmol) and Cs₂CO₃ (149.0 mg, 0.46 mmol). Thereaction mixture was stirred at 100° C. overnight under N₂ atmosphereand concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (MeOH/DCM (v/v)=1/20) to give the title compoundas a white solid (66.1 mg, 56%).

MS (ESI, pos. ion) m/z: 520.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 520.2077 [M+H]⁺; calculated value forC₂₄H₂₇ClN₁₁O [M+H]⁺ is 520.2089;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.90 (s, 1H), 8.66 (d, J=7.4 Hz, 1H),8.36 (d, J=1.8 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.43 (d,J=9.8 Hz, 1H), 7.26 (dd, J=7.5, 2.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H),4.67-4.62 (m, 3H), 4.46-4.33 (m, 1H), 3.22 (t, J=12.3 Hz, 2H), 2.82 (s,2H), 2.06 (d, J=10.9 Hz, 2H), 1.69 (m, 2H), 1.14 (s, 6H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 164.8, 159.1, 157.9, 157.3, 153.8,151.8, 142.5, 131.5, 128.9, 128.3, 117.9, 111.6, 108.2, 105.5, 99.2,69.8, 48.9, 44.3, 42.7, 30.9, 29.7.

Example 786-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(109.1 mg, 0.31 mmol) and1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol(100.1 mg, 0.49 mmol) in 1,4-dioxane (4 mL) were added Pd(OAc)₂ (7.2 mg,0.03 mmol), BINAP (20.3 mg, 0.03 mmol) and K₂CO₃ (87.0 mg, 0.63 mmol).The reaction mixture was stirred at 100° C. overnight under N₂atmosphere and concentrated in vacuo. The residue was purified by asilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as a white solid (76.4 mg, 47%).

MS (ESI, pos. ion) m/z: 519.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.2162 [M+H]⁺; calculated value forC₂₅H₂₈ClN₁₀O [M+H]⁺ is 519.2136;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.89 (s, 1H), 8.65 (d, J=7.4 Hz, 1H),8.50 (d, J=2.1 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.07 (s, 1H), 7.85 (dd,J=9.1, 2.3 Hz, 1H), 7.25 (dd, J=7.5, 2.1 Hz, 1H), 7.15 (d, J=7.8 Hz,1H), 7.00 (d, J=9.1 Hz, 1H), 4.62 (s, 1H), 4.56 (d, J=13.1 Hz, 2H),4.39-4.30 (m, 1H), 3.12 (t, J=12.4 Hz, 2H), 2.82 (s, 2H), 2.01 (d,J=10.7 Hz, 2H), 1.69-1.58 (m, 2H), 1.14 (s, 6H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 164.8, 159.5, 157.9, 157.3, 153.8,153.1, 151.9, 142.5, 140.4, 128.3, 119.2, 108.2, 107.0, 105.5, 99.1,95.3, 69.8, 49.1, 44.3, 42.7, 31.0, 29.7.

Example 796-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(60 mg, 0.17 mmol) and1-(6-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol (50mg, 0.24 mmol) in 1,4-dioxane (2 mL) were added Pd(OAc)₂ (4 mg, 0.02mmol), BINAP (11 mg, 0.02 mmol) and Cs₂CO₃ (112 mg, 0.34 mmol). Thereaction mixture was stirred at 100° C. for 2 h under N₂ atmosphere andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/30) to give the title compound as acreamy white solid (69 mg, 77%).

MS (ESI, pos. ion) m/z: 520.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 520.2098 [M+H]⁺; calculated value forC₂₄H₂₇ClN₁₁O [M+H]⁺ is 520.2089;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.61 (s, 1H), 9.56 (s, 1H), 8.04 (s,1H), 7.88 (d, J=9.7 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.68 (s, 1H), 7.43(d, J=9.8 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 4.65 (d, J=12.5 Hz, 2H), 4.54(s, 1H), 4.44-4.32 (m, 1H), 3.22 (t, J=12.6 Hz, 2H), 2.85 (s, 2H), 2.05(d, J=11.1 Hz, 2H), 1.74-1.64 (m, 2H), 1.13 (s, 6H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 164.1, 159.1, 158.0, 157.3, 153.9,146.9, 131.5, 129.9, 128.8, 125.7, 117.9, 116.9, 115.1, 111.6, 104.6,69.7, 44.3, 43.1, 31.4, 30.9, 29.7.

Example 806-(4-((5-chloro-2-((3-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) ethyl2-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-3-yl)acetate

To a solution of ethyl 2-(7-bromoimidazo[1,2-a]pyridin-3-ypacetate (4.70g, 17.0 mmol) and diphenylmethanimine (3.60 g, 20.0 mmol) in 1,4-dioxane(60 mL) were added Pd₂(dba)₃ (1.47 g, 1.61 mmol), BINAP (1.02 g, 1.64mmol) and Cs₂CO₃ (10.80 g, 33.1 mmol). The reaction mixture was stirredat 100° C. for 8 h under N₂ atmosphere and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (EtOAc/PE(v/v)=1/1) to give the title compound as a yellow solid (4.10 g, 64%).

MS (ESI, pos. ion) m/z: 384.2 [M+H]⁺.

Step 2) ethyl 2-(7-aminoimidazo[1,2-a]pyridin-3-yl)acetate

To a solution of ethyl2-(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-3-yl)acetate (3.10g, 2.53 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (4N,10 mL, 40 mmol). The reaction mixture was stirred at rt for 2 h andconcentrated in vacuo. The residue was adjusted to pH=8 with a saturatedNaHCO₃ aqueous solution and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (MeOH (7M NH₃)/DCM(v/v)=1/30) to give the title compound as a brown solid (900 mg, 51.8%).

MS (ESI, pos. ion) m/z: 220.2 [M+H]⁺.

Step 3) 1-(7-aminoimidazo[1,2-a]pyridin-3-yl)-2-methylpropan-2-ol

To a solution of ethyl 2-(7-aminoimidazo[1,2-a]pyridin-3-yl)acetate (900mg, 3.07 mmol) in THF (20 mL) was added a solution of methylmagnesiumbromide (3.0 M in Et₂O, 15 mL, 45 mmol) dropwise at −78° C. under N₂atmosphere. After addition, the reaction mixture was warmed up to 0° C.,stirred for 5 h and quenched with water (20 mL), then concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH (7M NH3)/DCM (v/v)=1/20) to give the title compound as a yellowsolid (230 mg, 27.3%).

MS (ESI, pos. ion) m/z: 206.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.20 (d, J=7.4 Hz, 1H), 7.10 (s, 1H),6.45 (dd, J=7.4, 2.0 Hz, 1H), 6.38 (d, J=2.0 Hz, 1H), 5.93 (s, 2H), 2.85(s, 2H), 1.13 (s, 6H).

Step 4)6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)imidazo[1,2-b]pyridazin-7-yl]amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(70 mg, 0.20 mmol) and1-(7-aminoimidazo[1,2-a]pyridin-3-yl)-2-methylpropan-2-ol (60 mg, 0.29mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)₂ (5 mg, 0.022 mmol),BINAP (12 mg, 0.019 mmol) and Cs₂CO₃ (130 mg, 0.40 mmol). The reactionmixture was stirred at 100° C. for 2 h under N₂ atmosphere andconcentrated in vacuo. The residue was purified by a silica column gelchromatography (MeOH/DCM (v/v)=1/30) to give the title compound as awhite solid (25 mg, 24.1% yield).

MS (ESI, pos. ion) m/z: 519.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.2134 [M+H]⁺; calculated value forC₂₅H₂₈ClN₁₀O [M+H]⁺ is 519.213;

¹H NMR (600 MHz, CDCl₃+CD₃OD) δ (ppm): 8.22 (s, 1H), 8.09 (s, 1H), 7.82(s, 1H), 7.39 (d, J=9.2 Hz, 1H), 7.31-7.19 (m, 2H), 6.92 (s, 1H),4.41-4.37 (m, 3H), 3.34-3.30 (m, 2H), 2.89 (s, 2H), 2.24-2.20 (m, 2H),1.53-1.49 (m, 2H), 1.20 (s, 6H);

¹³C NMR (150 MHz, CDCl₃+CD₃OD): δ (ppm) 158.5, 157.3, 157.2, 152.7,130.8, 123.0, 129.9, 128.6, 125.5, 121.8, 116.9, 110.6, 108.9, 106.3,71.2, 51.7, 43.5, 37.1, 31.3, 29.0.

Example 814-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)benzonitrile

To a solution of2-(7-((5-chloro-4-(piperidin-4-ylamino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol(0.10 g, 0.25 mmol) and 4-fluorobenzonitrile (36.5 mg, 0.30 mmol) inDMSO (5 mL) was added K₂CO₃ (68.0 mg, 0.49 mmol). The reaction mixturewas stirred at 100° C. for 8 h, cooled down to rt and quenched withwater (10 mL), then extracted with DCM (50 mL×4). The combined organicphases were washed with brine (100 mL×3), dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/10) to give the title compound as awhite solid (45.0 mg, 36%).

MS (ESI, pos, ion): 504.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 504.2022 [M+H]⁺; calculated value forC₂₅H₂₇ClN₉O [M+H]⁺ is 504.2027;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.87 (s, 1H), 8.67 (d, J=7.4 Hz, 1H),8.33 (d, J=1.7 Hz, 1H), 8.07 (s, 1H), 7.58 (d, J=8.9 Hz, 2H), 7.29 (dd,J=7.5, 2.1 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.08 (d, J=8.9 Hz, 2H),4.33-4.20 (m, 1H), 4.04 (d, J=13.1 Hz, 2H), 3.08 (t, J=12.3 Hz, 2H),1.99 (d, J=13.7 Hz, 2H), 1.77-1.67 (m, 2H), 1.51 (s, 6H);

¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 172.7, 157.9, 157.4, 153.7, 153.4,152.0, 142.4, 133.8, 128.6, 120.6, 114.8, 108.4, 105.6, 99.4, 98.2,68.6, 49.1, 46.9, 30.6, 30.1.

Example 822-(7-((5-chloro-4-((1-(6-cyanopyridazin-3-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N-methylacetamide

Step 1) ethyl 3-(methylamino)-3-oxopropanoate

To a solution of methanamine hydrochloride (2.24 g, 33.2 mmol) in THF(50 mL) was added KOH (4.09 g, 73.1 mmol). The reaction was cooled to 0°C. and added ethyl 3-chloro-3-oxo-propanoate (5.00 g, 33.2 mmol) slowly.The reaction was warmed to rt and stirred overnight. The reaction wasquenched with water (20 mL), then extracted with EtOAc (100 mL×4). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bya silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give thetitle compound as yellow liquid (0.89 g, 18.6%).

MS (ESI, pos. ion) m/z: 146.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.98 (s, 1H), 4.07 (q, J=7.1 Hz, 2H),3.19 (s, 2H), 2.59 (d, J=4.6 Hz, 3H), 1.18 (t, J=7.1 Hz, 3H).

Step 2) 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N-methylacetamide

To a solution of ethyl 3-(methylamino)-3-oxopropanoate (0.49 g, 3.38mmol) in MeOH (20 mL) were added NaOH (0.14 g, 3.38 mmol) and1,2,4-triaminopyridin-1-ium 2,4,6-trimethylbenzenesulfonate (0.50 g,1.54 mmol). The reaction was refluxed overnight and then concentrated invacuo. The residue was purified by a silica gel column chromatography(DCM/MeOH (v/v)=1/10) to give the title compound as a yellow solid (0.12g, 39.4%).

MS (ESI, pos. ion) m/z: 206.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.36 (d, J=7.3 Hz, 1H), 7.92 (s, 1H),6.48 (dd, J=7.3, 2.2 Hz, 1H), 6.42 (d, J=1.8 Hz, 1H), 6.11 (s, 2H), 3.48(s, 2H), 2.60 (d, J=4.6 Hz, 3H).

Step 3)2-(7-((5-chloro-4-((1-(6-cyanopyridazin-3-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N-methylacetamide

To a solution of2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N-methylacetamide (0.11g, 0.54 mmol) in 1,4-dioxane (5 mL) were added6-[4-[(2,5-dichloropyrimidin-4-yl)amino]-1-piperidyllpyridazine-3-carbonitrile(0.15 g, 0.43 mmol), BINAP (0.031 g, 0.05 mmol), Pd(OAc)₂ (0.011 g, 0.05mmol) and Cs₂CO₃ (0.35 g, 1.07 mmol). The reaction was refluxed for 1 hand then concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (DCM/MeOH (v/v)=1/20) to give the title compoundas a yellow solid (0.12 g, 43.3%).

MS (ESI, pos. ion) m/z: 519.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.1874 [M+H]⁺; calculated value forC₂₃H₂₄ClN₁₂O [M+H]⁺ is 519.1884;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.91 (s, 1H), 8.68 (d, J=7.5 Hz, 1H),8.30 (d, J=1.7 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J=4.3 Hz, 1H), 7.89 (d,J=9.7 Hz, 1H), 7.45 (d, J=9.7 Hz, 1H), 7.33 (dd, J=7.5, 2.1 Hz, 1H),7.13 (d, J=7.8 Hz, 1H), 4.65 (d, J=12.9 Hz, 2H), 4.45-4.34 (m, 1H), 3.59(s, 2H), 3.24 (t, J=12.1 Hz, 2H), 2.58 (d, J=4.6 Hz, 3H), 2.06 (d,J=10.7 Hz, 2H), 1.71-1.69 (m, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 168.52, 168.51, 162.17, 159.07,157.89, 157.32, 153.75, 152.19, 142.65, 131.58, 128.82, 128.43, 117.92,111.62, 108.38, 105.62, 98.99, 48.71, 44.29, 36.62, 30.87, 26.18.

Example 837-((5-chloro-4-((1-(5-cyanopyridin-2-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1) ethyl 2-(dimethylamino)-2-oxoacetate

To a solution of ethyl oxalyl monochloride (2.77 g, 20.3 mmol) in THF(10 mL) were added dropwise a solution of dimethylamine in THF (10 mL,20 mmol, 2 mol/L) and TEA (2.23 g, 22.0 mmol) at 0° C. The reaction wasstirred at 0° C. overnight and diluted with water (40 mL), the aqueousphase was extracted with EtOAc (50 mL×3). The organic layers were driedwith Na₂SO₄ and concentrated in vacuo to give the title compound asyellowish-brown liquid (1.316 g, 45.33%), which was used for the nextstep without further purification.

MS (ESI, pos.ion) m/z: 146.1 [M+H]⁺.

Step 2)7-bromo-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a suspension of 1,2-diamino-4-bromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (2.02 g, 5.20 mmol) and sodium hydroxide(217.4 mg, 5.435 mmol) in EtOH (20 mL) was added ethyl2-(dimethylamino)-2-oxoacetate (1.316 g, 9.066 mmol). The reaction wasstirred at reflux overnight and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc/PE (v/v)=4/1) togive the title compound as a white solid (446 mg, 31.9%).

MS (ESI, pos.ion) m/z: 269.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.46 (d, J=7.3 Hz, 1H), 7.97 (d, J=1.3Hz, 1H), 7.21 (dd, J=7.2, 2.0 Hz, 1H), 3.25 (s, 3H), 3.18 (s, 3H).

Step 3)7-((diphenylmethylene)amino)-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of7-bromo-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (446mg, 1.6574 mmol) and diphenylmethanimine (403.4 mg, 2.226 mmol) in1,4-dioxane (20 mL) were added BINAP (103.5 mg, 0.1662 mmol), Pd₂(dba)₃(146.7 mg, 0.1602 mmol) and Cs₂CO₃ (1.087 g, 3.336 mmol). The reactionwas stirred at reflux for 8 h, then cooled down to rt and concentratedin vacuo. The residue was diluted with (MeOH/DCM (v/v)=1/10, 50 mL). Theresulted was filtered. The filter cake was washed with DCM (50 mL×2).The filtrate was concentrated in vacuo to give the title compound asreddish brown solid-liquid mixture which was used for the next stepwithout further purification.

MS (ESI, pos.ion) m/z: 370.2[M+H]⁺.

Step 4)7-amino-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

A suspension of7-((diphenylmethylene)amino)-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide(612.2 mg, 1.657 mmol) and HCl in EtOAc (20 mL, 60 mmol, 3 mol/L) wasstirred at rt overnight. The reaction was concentrated directly in vacuoand added a saturated Na₂CO₃ aqueous solution to adjust pH=9. Themixture was concentrated in vacuo, the residue was purified by a silicagel column chromatography (3 M NH3 in MeOH/DCM (v/v)=1/25) to give thetitle compound as a light yellow solid (298 mg, 87.62%).

MS (ESI, pos.ion) m/z: 206.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.46 (d, J=7.4 Hz, 1H), 6.59 (dd,J=7.4, 2.3 Hz, 1H), 6.50 (d, J=2.0 Hz, 1H), 6.27 (s, 2H), 3.01 (s, 3H),2.99 (s, 3H).

Step 5)7-((5-chloro-4-((1-(5-cyanopyridin-2-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a suspension of6-[4-[(2,5-dichloropyrimidin-4-yl)amino]-1-piperidyl]pyridine-3-carbonitrile(256.7 mg, 0.7351 mmol) and7-amino-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (146.4mg, 0.7134 mmol) in 1,4-dioxane (20 mL) were added BINAP (44.1 mg,0.0708 mmol), Pd(OAc)₂ (17.7 mg, 0.0788 mmol) and Cs₂CO₃ (468.2 mg,1.437 mmol). The reaction was stirred at reflux overnight andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/35) to give the title compound as anoff-white solid (92 mg, 24.16%).

MS (ESI, pos.ion) m/z: 518.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 518.1924 [M+H]⁺; calculated value forC₂₄H₂₅ClN₁₁O [M+H]⁺ is 518.1932;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.02 (s, 1H), 8.77 (d, J=7.5 Hz,1H), 8.50 (d, J=2.1 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.09 (s, 1H), 7.85(dd, J=9.1, 2.3 Hz, 1H), 7.38 (dd, J=7.5, 2.1 Hz, 1H), 7.17 (d, J=7.8Hz, 1H), 7.01 (d, J=9.2 Hz, 1H), 4.56 (d, J=12.9 Hz, 2H), 4.40-4.28 (m,1H), 3.12 (t, J=12.4 Hz, 2H), 3.01 (d, J=9.8 Hz, 6H), 2.01 (d, J=10.2Hz, 2H), 1.64 (qd, J=12.5, 3.6 Hz, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 162.21, 159.10, 158.95, 157.38,156.89, 153.33, 152.65, 151.08, 142.87, 140.02, 128.58, 118.82, 109.45,106.53, 105.33, 98.87, 94.87, 48.65, 43.85, 38.02, 34.70, 30.51.

Example 846-(4-((5-chloro-2-((2-(3-hydroxyazetidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) ethyl 2-(3-hydroxyazetidin-1-yl)-2-oxoacetate

To a solution of azetidin-3-ol hydrochloride (800.8 mg, 7.309 mmol) inTHF (15 mL) were added ethyl 2-chloro-2-oxo-acetate (1.37 g, 10.0 mmol)and triethylamine (3 mL, 21.6 mmol) at 0° C. The mixture was stirred at0° C. overnight. The resulted mixture was diluted with water (50 mL) andextracted with DCM (100 mL×3). The combined organic phases were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as brown oil (1.10 g, 63.3%).

MS (ESI, pos. ion) m/z: 174.0 [M+H]⁺;

¹HNMR (400 MHz, CDCl₃) δ (ppm): 4.68-4.67 (m, 1H), 4.66-4.65 (m, 2H),4.32-4.30 (m, 2H), 3.95-3.92 (m, 2H), 1.33 (t, J=7.1 Hz, 3H).

Step 2)(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone

To a solution of pyridin-1-ium-1,2,4-triamine2,4,6-trimethylbenzenesulfonate (350 mg, 1.079 mmol) in ethanol (15 mL)were added ethyl 2-(3-hydroxyazetidin-1-yl)-2-oxo-acetate (450 mg,2.5986 mmol) and sodium hydroxide (51.4 mg, 1.29 mmol). The mixture wasstirred at 80° C. overnight and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (MeOH/DCM (v/v)=1/20) togive the title compound as a pale yellow solid (150.0 mg, 59.6%).

MS (ESI, pos. ion) m/z: 234.0[M+H]⁺;

¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.48 (d, J=7.4 Hz, 1H), 6.64 (dd,J=7.4, 2.2 Hz, 1H), 6.52 (d, J=1.9 Hz, 1H), 6.31 (s, 2H), 5.76 (d, J=6.4Hz, 1H), 4.74-4.65 (m, 1H), 4.56-4.45 (m, 1H), 4.29-4.19 (m, 2H),3.81-3.73 (m, 1H).

Step 3)6-(4-((5-chloro-2-((2-(3-hydroxyazetidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-[4-[(2,5-dichloropyrimidin-4-yl)amino]-1-piperidyl]pyridazine-3-carbonitrile(102.0 mg, 0.2913 mmol) in 1,4-dioxane (10 mL) were added(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(3-hydroxyazetidin-1-yl)methanone(132.8 mg, 0.5694 mmol), palladium diacetate (9.4 mg, 0.042 mmol),(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (17.9 mg, 0.0287 mmol)and potassium carbonate (89.0 mg, 0.644 mmol). The mixture was stirredat 100° C. under nitrogen for 2 h and concentrated in vacuo. The residuewas purified by a silica gel column chromatography (MeOH/DCM (v/v)=1/20)to give the title compound as a pale yellow solid (79.1 mg, 49.6%).

MS (ESI, pos.ion) m/z: 547.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 547.1830 [M+H]⁺; calculated value forC₂₄H₂₄ClN₁₂O₂ [M+H]⁺ is 547.1828;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.06 (s, 1H), 8.79 (d, J=7.5 Hz,1H), 8.53 (s, 1H), 8.11 (s, 1H), 7.87 (d, J=9.7 Hz, 1H), 7.45 (d, J=9.7Hz, 1H), 7.38 (dd, J=7.5, 1.7 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 5.66 (d,J=6.5 Hz, 1H), 4.76-4.69 (m, 2H), 4.75-4.65 (m, 1H), 4.47-4.33 (m, 2H),4.29-4.17 (m, 2H), 3.80-3.73 (m, 1H), 3.29-3.20 (m, 2H), 2.16-2.05 (m,2H), 1.80-1.66 (m, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 159.9, 159.1, 158.2, 157.8, 157.3,153.9, 151.9, 143.2, 131.6, 129.1, 128.9, 118.0, 111.6, 110.4, 105.7,99.4, 63.7, 61.1, 58.6, 49.1, 44.4, 30.9.

Example 857-((5-chloro-4-((1-(6-cyanopyridazin-3-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1)7-((5-chloro-4-((1-(6-cyanopyridazin-3-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a suspension of6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(259.4 mg, 0.7407 mmol) and7-amino-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (146.8mg, 0.7153 mmol) in 1,4-dioxane (20 mL) were added BINAP (45.2 mg,0.0726 mmol), Pd(OAc)₂ (17.8 mg, 0.0793 mmol) and Cs₂CO₃ (471.6 mg,1.447 mmol). The reaction was stirred at reflux overnight andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/35) to give the title compound as awhite solid (144 mg, 37.46%).

MS (ESI, pos.ion) m/z: 519.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 519.1870 [M+H]⁺; calculated value forC₂₃H₂₄ClN₁₂O [M+H]⁺ is 519.1885;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.03 (s, 1H), 8.78 (d, J=7.5 Hz,1H), 8.46 (d, J=1.3 Hz, 1H), 8.11 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.44(d, J=9.7 Hz, 1H), 7.39 (dd, J=7.5, 1.8 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H),4.65 (d, J=12.5 Hz, 2H), 4.46-4.32 (m, 1H), 3.23 (t, J=12.4 Hz, 2H),3.01 (d, J=10.1 Hz, 6H), 2.07 (d, J=11.1 Hz, 2H), 1.70 (qd, J=12.4, 3.2Hz, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 162.22, 159.11, 158.65, 157.38,156.90, 153.36, 151.08, 142.87, 131.14, 128.60, 128.41, 117.48, 111.20,109.45, 105.34, 98.88, 48.44, 43.88, 38.02, 34.68, 30.43.

Example 867-((5-chloro-4-((1-(6-cyanopyridazin-3-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-N-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1) ethyl 2-(cyclopropylamino)-2-oxoacetate

To a solution of cyclopropanamine (4.18 g, 73.2 mmol) in THF (100 mL)was added Et₃N (14.79 g, 146.4 mmol). The reaction was cooled to 0° C.and added ethyl 2-chloro-2-oxoacetate (10.00 g, 73.2 mmol) slowly. Thereaction was warmed to rt and stirred overnight. The reaction wasquenched with water (20 mL), extracted with EtOAc (100 mL×4). Thecombined organic layers were washed with saturated NaCl (100 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (EtOAc/PE(v/v)=1/10) to give the title compound as yellow liquid (7.90 g, 68.2%).

MS (ESI, pos. ion) m/z: 158.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.31 (q, J=7.1 Hz, 2H), 2.86-2.75 (m,1H), 1.36 (t, J=7.1 Hz, 3H), 0.89-0.80 (m, 2H), 0.65-0.56 (m, 2H).

Step 2)7-amino-N-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of ethyl 2-(cyclopropylamino)-2-oxoacetate (2.13 g, 13.56mmol) in MeOH (20 mL) were added NaOH (0.54 g, 13.56 mmol) and1,2,4-triaminopyridin-1-ium 2,4,6-trimethylbenzenesulfonate (2.00 g,6.16 mmol). The mixture was refluxed overnight, then concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/10) to give the title compound as yellow liquid (0.18g, 13.5%).

MS (ESI, pos. ion) m/z: 218.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.54 (d, J=4.6 Hz, 1H), 8.46 (t,J=9.7 Hz, 1H), 6.63 (dd, J=7.4, 2.2 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H),6.30 (s, 2H), 2.92-2.78 (m, 1H), 0.66-0.64 (m, 4H).

Step 3)7-((5-chloro-4-((1-(6-cyanopyridazin-3-yl)piperidin-4-yl)amino)pyrimidin-2-yl)amino)-N-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of7-amino-N-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (0.11g, 0.51 mmol) in 1,4-dioxane (5 mL) were added6-[4-[(2,5-dichloropyrimidin-4-yl)amino]-1-piperidyl]pyridazine-3-carbonitrile(0.12 g, 0.35 mmol), BINAP (0.031 g, 0.05 mmol), Pd(OAc)₂ (0.011 g, 0.05mmol) and Cs₂CO₃ (0.331 g, 1.01 mmol). The mixture was refluxed for 1 hand then concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (MeOH/DCM (v/v)=1/20) to give the title compoundas a yellow solid (0.085 g, 31.8%).

MS (ESI, pos. ion) m/z: 531.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 531.1876 [M+H]⁺; calculated value forC₂₄H₂₄ClN₁₂O [M+H]⁺ is 531.1884;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.02 (s, 1H), 8.79 (d, J=7.5 Hz,1H), 8.60 (d, J=4.6 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H), 8.12 (s, 1H), 7.88(d, J=9.7 Hz, 1H), 7.51-7.46 (m, 1H), 7.45 (d, J=9.8 Hz, 1H), 7.17 (d,J=7.8 Hz, 1H), 4.64 (d, J=12.8 Hz, 2H), 4.39 (dd, J=7.4, 3.7 Hz, 1H),3.23 (t, J=12.2 Hz, 2H), 2.92-2.80 (m, 1H), 2.05 (d, J=10.8 Hz, 2H),1.71-1.69 (m, 2H), 0.74-0.64 (m, 2H), 0.66-0.57 (m, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 160.98, 159.13, 158.78, 157.74,157.37, 153.52, 151.91, 143.46, 131.55, 129.19, 128.83, 117.93, 111.63,110.30, 106.08, 99.40, 55.38, 48.58, 44.25, 30.84, 23.21, 6.22.

Example 876-(4-((5-chloro-2-((3-(3-hydroxyazetidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) (Z)-4-bromo-2-hydrazono-1,2-dihydropyridine

To a solution of 4-bromo-2-fluoropyridine (5.22 g, 29.7 mmol) inpyridine (15 mL) was added hydrazine hydrate (13.5 mL, 273 mmol). Themixture was stirred at 75° C. for 2 h and concentrated. The residue wasdiluted with water (10 mL) and stirred for 0.5 h. The mixture wasfiltered. The filter cake was washed with water (1 mL×3) and dried togive the title compound as a white solid (4.61 g, 82.7%).

MS (ESI, pos. ion) m/z: 188.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.85 (d, J=5.3 Hz, 1H), 7.71 (s, 1H),6.92 (d, J=1.5 Hz, 1H), 6.70 (dd, J=5.3, 1.7 Hz, 1H), 4.20 (s, 2H).

Step 2) ethyl 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate

To a solution of (Z)-4-bromo-2-hydrazono-1,2-dihydropyridine (2.03 g,10.8 mmol) in methanol (30 mL) was added ethyl 2-oxoacetate (2.17 g,21.3 mmol). The mixture was stirred at 70° C. for 1.5 h and concentratedin vacuo. The mixture of residue and (diacetoxyiodo)benzene (3.77 g,11.7 mmol) were dissolved in DCM (25 mL) and stirred at rt overnight andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (EtOAc/PE (v/v)=2/5) to give the title compound as a paleyellow solid (1.27 g, 43.6%).

MS (ESI, pos. ion) m/z: 270.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.03 (d, J=7.4 Hz, 1H), 8.14 (d, J=0.8Hz, 1H), 7.19 (dd, J=7.4, 1.7 Hz, 1H), 4.58 (q, J=7.1 Hz, 2H), 1.51 (t,J=7.1 Hz, 3H).

Step 3)(7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(3-hydroxyazetidin-1-yl)methanone

To a solution of ethyl7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (1.27 g, 4.70 mmol)in ethanol (15 mL) in microwave tube were added azetidin-3-olhydrochloride (1.29 g, 11.8 mmol) and triethylamine (3.3 mL, 24 mmol).The mixture was stirred at 80° C. overnight and concentrated in vacuo.The residue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as a pale yellow solid (1.21 g,86.6%).

MS (ESI, pos. ion) m/z: 297.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.11 (d, J=7.1 Hz, 1H), 8.38 (d,J=0.9 Hz, 1H), 7.35 (dd, J=7.4, 1.8 Hz, 1H), 5.85 (d, J=6.2 Hz, 1H),4.90-4.82 (m, 1H), 4.63-4.54 (m, 1H), 4.41-4.32 (m, 2H), 3.91-3.84 (m,1H).

Step 4)(7-((diphenylmethylene)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(3-hydroxyazetidin-1-yl)methanone

To a solution of(7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(3-hydroxyazetidin-1-yl)methanone(1.21 g, 4.07 mmol) in 1,4-dioxane (25 mL) were addeddiphenylmethanimine (1.4 mL, 8.3 mmol),tris(Dibenzylideneacetone)Dipalladium (375.4 mg, 0.410 mmol),(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (255.8 mg, 0.4108mmol) and cesium carbonate (2.67 g, 8.19 mmol). The mixture was stirredat 100° C. under nitrogen for 3 h and concentrated in vacuo. The residuewas purified by a silica gel column chromatography (MeOH/DCM (v/v)=1/20)to give the title compound as brown oil (1.26 g, 77.9%).

MS (ESI, pos.ion) m/z: 398.1 [M+H]⁺.

Step 5)(7-amino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(3-hydroxyazetidin-1-yl)methanone

To a solution of(7-((diphenylmethylene)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(3-hydroxyazetidin-1-yl)methanone(410.3 mg, 1.010 mmol) in DCM (25 mL) was added HCl/EtOAc (3.4 mL, 10mmol). The mixture was stirred at rt for 1 h and added a saturatedNaHCO₃ aqueous solution to adjust to pH=8. The resulted mixture wasconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (MeOH/DCM (v/v)=1/20) to give the title compound as ayellow solid (230.5 mg, 97.9%).

MS (ESI, pos.ion) m/z: 234.0 [M+H]⁺.

Step 6)6-(4-((5-chloro-2-((3-(3-hydroxyazetidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of6-[4-[(2,5-dichloropyrimidin-4-yl)amino]-1-piperidyl]pyridazine-3-carbonitrile(200.2 mg, 0.5717 mmol) in 1,4-dioxane (20 mL) were added(7-amino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(3-hydroxyazetidin-1-yl)methanone(220.5 mg, 0.9454 mmol), palladium diacetate (20.2 mg, 0.090 mmol),(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (39.1 mg, 0.0628 mmol)and potassium carbonate (161.5 mg, 1.169 mmol). The mixture was stirredat 100° C. under nitrogen for 3 h and concentrated in vacuo. The residuewas purified by a silica gel column chromatography (MeOH/DCM (v/v)=1/15)to give the title compound as a pale yellow solid (133.4 mg, 42.7%).

MS (ESI, pos.ion) m/z: 547.2[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 547.1823 [M+H]⁺; calculated value forC₂₄H₂₄ClN₁₂O₂ [M+H]⁺ is 547.1828;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.20 (s, 1H), 9.06 (d, J=7.6 Hz,1H), 8.58 (s, 1H), 8.14 (s, 1H), 7.89 (d, J=9.7 Hz, 1H), 7.47 (d, J=9.7Hz, 1H), 7.29 (dd, J=21.7, 7.6 Hz, 2H), 4.86-4.78 (m, 1H), 4.74-4.64 (m,2H), 4.62-4.55 (m, 1H), 4.48-4.38 (m, 1H), 4.37-4.30 (m, 2H), 3.90-3.82(m, 1H), 3.32-3.25 (m, 2H), 2.14-2.05 (m, 2H), 1.78-1.65 (m, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 159.1, 157.6, 157.4, 157.4, 153.7,151.0, 142.5, 138.4, 131.6, 128.9, 126.7, 117.9, 111.9, 111.7, 106.1,95.6, 63.9, 61.4, 58.7, 44.3, 30.9.

Example 886-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-fluoropiperidin-1-yl)pyridazine-3-carbonitrile

Step 1) tert-butyl (mesitylsulfonyl)oxycarbamate

To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (20 g, 92.9mmol) in EtOAc (200 mL) were added tert-butyl hydroxycarbamate (12.21 g,91.7 mmol) and Et₃N (11.6 g, 115 mmol). The reaction mixture was stirredat 0° C. for 2 h, then added water (100 mL), and the resulted mixturewas extracted with EtOAc (100 mL×3), the combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude product was used for next step withoutfurther purification.

Step 2) O-(mesitylsulfonyl)hydroxylamine

To a solution of tert-butyl (mesitylsulfonyl)oxycarbamate (28 g, 88.8mmol) in EtOAc (200 mL) was added H₂SO₄ (18.4 g, 98% mass). The mixturewas stirred at 5° C. for 8 h, then added water (200 mL), the resultedmixture was adjusted to pH=8 with NaHCO₃ soild, the organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was used for next step without further purification.

Step 3) 1,2,4-triaminopyridin-1-ium 2,4,6-trimethylbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (20.0 g, 92.0 mmol) inEtOAc (200 mL) was added pyridine-2,4-diamine (4.0 g, 37.0 mmol). Thereaction mixture was stirred at 5° C. for 1 h. The mixture was filteredto give the title compound as a yellow solid (6.4 g, 53.7%).

MS (ESI, pos. ion) m/z: 125.1 [M+H]⁺.

Step 4) 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of 1,2,4-triaminopyridin-1-ium2,4,6-trimethylbenzenesulfonate (6.4 g, 0.487 mmol) in EtOH (50 mL) wereadded sodium hydroxide (1.6 g, 39 mmol) and ethyl2-hydroxy-2-methyl-propanoate (5.2 g, 39 mmol). The reaction was stirredat 80° C. for 1 h. The mixture were added sodium hydrate (1.6 g, 39mmol) and ethyl 2-hydroxy-2-methyl-propanoate (5.2 g, 39 mmol) once anhour for a total of three times. The mixture was filtered, and thefiltrate was concentrated in vacuo. The residue was purified by a flashcolumn chromatography (MeOH/DCM (v/v)=1/20) to give the title compoundas a yellow solid (2.3 g, 61.0%).

MS (ESI, pos. ion) m/z: 193.1 [M+H]⁺.

Step 5) tert-butyl4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-fluoropiperidine-1-carboxylate

To a solution of2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol (740 mg, 3.8mmol) in 1,4-dioxane (25 mL) were added Pd(OAc)₂ (90.0 mg, 0.38 mmol),BINAP (98%, 240 mg, 0.38 mmol) and cesium carbonate (98%, 2500 mg, 7.7mmol). The mixture was stirred at reflux for 2 h and concentrated invacuo. The residue was purified by a flash column chromatography(MeOH/DCM (v/v)=1/20) to give the title compound as a white solid (1.71g, 86.0%).

MS (ESI, pos. ion) m/z: 521.1 [M+H]⁺.

Step 6)2-(7-((5-chloro-4-((3-fluoropiperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol

To a solution of tert-butyl4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-fluoropiperidine-1-carboxylate(400 mg, 0.736 mmol) in CH₂Cl₂ (15 mL) was added hydrogen chlorideaqueous solution (2 mL, 10 mmol, 10 mol/L). The mixture was stirred atroom temperature for 1 h, then washed with saturated sodium carbonateaqueous solution. The organic layer was concentrated in vacuo. Theresidue was purified by a flash column chromatography (MeOH/DCM(v/v)=1/10) to give the title compound as a white solid (290 mg,88.38%).

MS (ESI, pos. ion) m/z: 421.2 [M+H]⁺.

Step 7)6-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-fluoropiperidin-1-yl)pyridazine-3-carbonitrile

To a solution of2-(7-((5-chloro-4-((3-fluoropiperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol(400 mg, 0.95 mmol) in MeOH (20 mL) was added6-chloropyridazine-3-carbonitrile (240 mg, 1.71 mmol). The reactionmixture was stirred at 80° C. for 8 h. The mixture was concentrated invacuo. The residue was purified by a flash column chromatography(MeOH/DCM (v/v)=1/20) to give the title compound as a white solid (410mg, 82.3%).

MS (ESI, pos. ion) m/z: 524.4 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 524.1842 [M+H]⁺; calculated value forC₂₃H₂₃ClFN₁₁O [M+H]⁺ is 524.9532;

¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (d, J=13.7 Hz, 2H), 8.69 (t, J=6.9 Hz,2H), 8.24 (dd, J=11.5, 1.7 Hz, 2H), 8.14 (d, J=5.9 Hz, 2H), 7.92 (dd,J=25.0, 9.7 Hz, 2H), 7.52 (dd, J=26.7, 9.7 Hz, 2H), 7.44-7.28 (m, 3H),7.04 (d, J=7.1 Hz, 1H), 5.10 (s, 2H), 4.99-4.81 (m, 2H), 4.82-4.75 (m,1H), 4.68-4.59 (m, 1H), 4.49 (d, J=12.4 Hz, 1H), 3.34 (s, 1H), 3.28 (dd,J=11.8, 7.3 Hz, 2H), 3.17 (d, J=5.1 Hz, 1H), 2.17-2.08 (m, 2H), 1.93 (d,J=10.4 Hz, 1H), 1.74 (d, J=9.4 Hz, 1H), 1.53 (s, 12H), 1.22 (s, 1H);

¹³C NMR (151 MHz, DMSO-d₆) δ 172.69, 172.66, 160.97, 159.95, 159.77,159.29, 158.72, 157.88, 157.79, 157.78, 157.68, 157.28, 156.91, 154.13,154.04, 153.91, 153.77, 151.96, 151.92, 144.61, 142.43, 142.40, 142.36,132.73, 131.89, 131.80, 131.58, 131.45, 130.53, 130.03, 129.78, 129.71,129.15, 129.07, 128.67, 128.61, 119.38, 117.81, 117.76, 117.68, 113.03,112.20, 112.10, 111.73, 110.21, 108.48, 108.42, 107.43, 105.81, 105.76,105.69, 101.11, 99.68, 99.63, 99.56, 91.13, 89.19, 89.01, 88.23, 88.13,87.99, 87.30, 87.05, 68.57, 68.39, 54.16, 52.73, 52.66, 52.61, 52.19,50.80, 50.74, 50.68, 50.24, 49.07, 48.03, 47.65, 47.47, 47.26, 47.17,47.07, 46.77, 43.68, 43.64, 43.60, 42.73, 40.46, 30.15, 30.12, 30.11,28.99, 25.27.

Example 896-(4-((5-chloro-2-((2-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)-3-fluoropiperidin-1-yl)nicotinonitrile

To a solution of2-(7-((5-chloro-4-((3-fluoropiperidin-4-yl)amino)pyrimidin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)propan-2-ol(300 mg, 0.712 mmol) in MeOH (15 mL) was added6-chloropyridine-3-carbonitrile (180 mg, 1.28 mmol). The reaction wasstirred at 80° C. for 8 h. The mixture was concentrated in vacuo, Theresidue was purified by a flash column chromatography (MeOH/DCM(v/v)=1/20) to give the title compound as a white solid (210 mg, 56.3%).

MS (ESI, pos. ion) m/z: 524.4 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 524.1842 [M+H]⁺; calculated value forC₂₄H₂₄ClFN₁₀O [M+H]⁺ is 524.9532;

¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (d, J=13.7 Hz, 2H), 8.69 (t, J=6.9 Hz,2H), 8.24 (dd, J=11.5, 1.7 Hz, 2H), 8.14 (d, J=5.9 Hz, 2H), 7.92 (dd,J=25.0, 9.7 Hz, 2H), 7.52 (dd, J=26.7, 9.7 Hz, 2H), 7.44-7.28 (m, 3H),7.04 (d, J=7.1 Hz, 1H), 5.10 (s, 2H), 4.99-4.81 (m, 2H), 4.82-4.75 (m,1H), 4.68-4.59 (m, 1H), 4.49 (d, J=12.4 Hz, 1H), 3.34 (s, 1H), 3.28 (dd,J=11.8, 7.3 Hz, 2H), 3.17 (d, J=5.1 Hz, 1H), 2.17-2.08 (m, 2H), 1.93 (d,J=10.4 Hz, 1H), 1.74 (d, J=9.4 Hz, 1H), 1.53 (s, 12H), 1.22 (s, 1H);

¹³C NMR (151 MHz, DMSO-d₆) δ 172.69, 172.66, 160.97, 159.95, 159.77,159.29, 158.72, 157.88, 157.79, 157.78, 157.68, 157.28, 156.91, 154.13,154.04, 153.91, 153.77, 151.96, 151.92, 144.61, 142.43, 142.40, 142.36,132.73, 131.89, 131.80, 131.58, 131.45, 130.53, 130.03, 129.78, 129.71,129.15, 129.07, 128.67, 128.61, 119.38, 117.81, 117.76, 117.68, 113.03,112.20, 112.10, 111.73, 110.21, 108.48, 108.42, 107.43, 105.81, 105.76,105.69, 101.11, 99.68, 99.63, 99.56, 91.13, 89.19, 89.01, 88.23, 88.13,87.99, 87.30, 87.05, 68.57, 68.39, 54.16, 52.73, 52.66, 52.61, 52.19,50.80, 50.74, 50.68, 50.24, 49.07, 48.03, 47.65, 47.47, 47.26, 47.17,47.07, 46.77, 43.68, 43.64, 43.60, 42.73, 40.46, 30.15, 30.12, 30.11,28.99, 25.27.

Example 906-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 1-(6-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol

To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (1.50 g, 7.57 mmol)in DMF (15 mL) were added 1-bromopropan-2-ol (2.01 g, 11.4 mmol) andcesium carbonate (3.71 g, 11.4 mmol). The mixture was stirred at 100° C.overnight and concentrated in vacuo. The residue was purified by asilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as a pale yellow solid (1.12 g, 57.7%).

MS (ESI, pos.ion) m/z: 256.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ (ppm) 8.47 (d, J=2.0 Hz, 1H), 8.45-8.43 (m,2H), 5.01 (d, J=5.0 Hz, 1H), 4.29 (dd, J=14.2, 3.1 Hz, 1H), 4.12-4.06(m, 1H), 4.01-3.94 (m, 1H), 1.11 (d, J=6.2 Hz, 3H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 154.9, 148.5, 144.5, 128.4, 122.5,113.4, 65.7, 52.4, 21.1.

Step 2)1-(6-((diphenylmethylene)amino)-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol

To a solution of 1-(6-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol(1.12 g, 4.37 mmol) in toluene (20 mL) were added Xantphos (256.1 mg,0.4426 mmol), Pd₂(dba)₃ (400.3 mg, 0.4372 mmol), t-BuONa (635.1 mg,6.609 mmol) and diphenylmethanimine (1.21 g, 6.68 mmol). The mixture wasstirred at 100° C. under nitrogen for 6 h and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/10) to give the title compound as a pale brown solid (446.5 mg,28.6%).

MS (ESI, pos.ion) m/z: 357.1 [M+H]⁺.

Step 3) 1-(6-amino-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol

To a solution of1-(6-((diphenylmethylene)amino)-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol(446.5 mg, 1.253 mmol) in THF (10 mL) was added HCl aqueous solution(1.0 mL, 12 mmol). The mixture was stirred at rt for 1 h andconcentrated in vacuo. The mixture was adjusted to pH=8 with saturatedNaHCO₃ aqueous solution and concentrated in vacuo. The residue waspurified by a flash column chromatography (MeOH/DCM (v/v)=1/10) to givethe title compound as a brown solid (117.8 mg, 48.9%).

MS (ESI, pos.ion) m/z: 193.2 [M+H]⁺.

Step 4)6-(4-((5-chloro-2-((1-(2-hydroxypropyl)-1H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of 1-(6-amino-1H-imidazo[4,5-b]pyridin-1-yl)propan-2-ol(117.8 mg, 0.6128 mmol) in 1,4-dioxane (15 mL) were added6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(150.1 mg, 0.4286 mmol), Pd(OAc)₂ (9.8 mg, 0.0436 mmol), BINAP (28.6 mg,0.0459 mmol) and cesium carbonate (210.6 mg, 0.6464 mmol). The mixturewas stirred at 100° C. for 3 h and concentrated in vacuo. The residuewas purified by a flash column chromatography (MeOH/DCM (v/v)=1/25) togive the title compound as a pale yellow solid (120.1 mg, 55.4%).

MS (ESI, pos.ion) m/z: 506.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 506.1927 [M+H]⁺; calculated value forC₂₃H₂₅ClN₁₁O [M+H]⁺ is 506.1932;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.40 (s, 1H), 8.59 (s, 1H), 8.49 (s,1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.43 (d, J=9.7Hz, 1H), 6.96 (d, J=7.4 Hz, 1H), 5.03 (d, J=3.8 Hz, 1H), 4.72-4.57 (m,2H), 4.41-4.27 (m, 1H), 4.25-4.15 (m, 1H), 4.14-4.02 (m, 2H), 3.22-3.11(m, 2H), 2.09-1.99 (m, 2H), 1.75-1.59 (m, 2H), 1.08 (d, J=5.1 Hz, 3H).

¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) 159.0, 158.7, 157.2, 153.9, 146.5,142.9, 137.6, 134.9, 133.5, 131.6, 128.8, 117.9, 117.9, 111.6, 104.0,72.7, 65.0, 50.6, 44.3, 31.0, 21.4.

Example 916-(4-((5-chloro-2-((3-(2-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 2-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)ethanol

To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (1.50 g, 7.57 mmol)in DMF (15 mL) were added 2-bromoethanol (1.42 g, 11.4 mmol) and cesiumcarbonate (3.71 g, 11.4 mmol). The mixture was stirred at 100° C. for 3h and concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (MeOH/DCM (v/v)=1/20) to give the title compoundas a pale yellow solid (1.06 g, 57.8%).

MS (ESI, pos.ion) m/z: 242.0 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ (ppm) 8.47 (s, 1H), 8.45 (d, J=2.0 Hz, 1H),8.36 (d, J=2.0 Hz, 1H), 5.03 (t, J=5.3 Hz, 1H), 4.32 (t, J=5.4 Hz, 2H),3.79 (q, J=5.3 Hz, 2H);

¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) 147.9, 146.3, 144.2, 136.7, 129.9,113.2, 59.5, 46.4.

Step 2)2-(6-((diphenylmethylene)amino)-3H-imidazo[4,5-b]pyridin-3-yl)ethanol

To a solution of 2-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)ethanol (1.06g, 4.38 mmol) in toluene (20 mL) were added Xantphos (256.2 mg, 0.4428mmol), Pd₂(dba)₃ (403.2 mg, 0.4403 mmol), t-BuONa (635.2 mg, 6.610 mmol)and diphenylmethanimine (1.21 g, 6.68 mmol). The mixture was stirred at100° C. under nitrogen atmosphere for 6 h and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (MeOH/DCM(v/v)=1/10) to give the title compound as a brown solid (694.4 mg,46.3%).

MS (ESI, pos.ion) m/z: 343.2 [M+H]⁺.

Step 3) 2-(6-amino-3H-imidazo[4,5-b]pyridin-3-yl)ethanol

To a solution of2-(6-((diphenylmethylene)amino)-3H-imidazo[4,5-b]pyridin-3-yl)ethanol(694.4 mg, 2.028 mmol) in THF (10 mL) was added HCl aqueous solution(1.7 mL, 20 mmol). The mixture was stirred at rt for 1 h andconcentrated in vacuo. The mixture was neutralized to pH=8 withsaturated NaHCO₃ aqueous solution and concentrated in vacuo. The residuewas purified by a flash column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as a brown solid (239.5 mg, 66.3%).

MS (ESI, pos.ion) m/z: 179.1 [M+H]⁺.

Step 4)6-(4-((5-chloro-2-((3-(2-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of 2-(6-amino-3H-imidazo[4,5-b]pyridin-3-yl)ethanol (219.0mg, 1.229 mmol) in 1,4-dioxane (15 mL) were added6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(155.0 mg, 0.4426 mmol), Pd(OAc)₂ (10.2 mg, 0.0454 mmol), BINAP (28.3mg, 0.0454 mmol) and cesium carbonate (220.4 mg, 0.6764 mmol). Themixture was stirred at 100° C. for 3 h and concentrated in vacuo. Theresidue was purified by a flash column chromatography (MeOH/DCM(v/v)=1/25) to give the title compound as a pale yellow solid (185.3 mg,85.1%).

MS (ESI, pos.ion) m/z: 492.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 492.1768 [M+H]⁺; calculated value forC₂₂H₂₃ClN₁₁O [M+H]⁺ is 492.1770;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.40 (s, 1H), 8.59 (d, J=1.4 Hz, 1H),8.51 (d, J=1.7 Hz, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.88 (d, J=9.7 Hz,1H), 7.44 (d, J=9.7 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 5.00 (t, J=5.3 Hz,1H), 4.70-4.60 (m, 2H), 4.41-4.32 (m, 1H), 4.28 (t, J=5.3 Hz, 2H),3.82-3.75 (m, 2H), 3.19-3.12 (m, 2H), 2.10-2.00 (m, 2H), 1.74-1.60 (m,2H);

¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 159.1, 158.7, 157.3, 153.9, 146.3,142.8, 137.6, 135.1, 133.5, 131.5, 128.8, 118.0, 117.9, 111.6, 104.0,59.7, 48.6, 46.2, 44.3, 31.0.

Example 926-(4-((5-chloro-2-((3-(2-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile

To a solution of 2-(6-amino-3H-imidazo[4,5-b]pyridin-3-yl)ethanol (123.5mg, 0.6931 mmol) in 1,4-dioxane (15 mL) were added6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile(200.1 mg, 0.5730 mmol), Pd(OAc)₂ (13.6 mg, 0.0606 mmol), BINAP (36.4mg, 0.0585 mmol) and cesium carbonate (286.3 mg, 0.8787 mmol). Themixture was stirred at 100° C. for 3 h and concentrated in vacuo. Theresidue was purified with flash column chromatography (MeOH/DCM(v/v)=1/25) to give the title compound as a pale yellow solid (95.6 mg,34.0%).

MS (ESI, pos.ion) m/z: 491.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 491.1822 [M+H]⁺, calculated value forC₂₃H₂₄ClN₁₀O [M+H]⁺ is 491.1818;

¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.39 (s, 1H), 8.59 (s, 1H), 8.50 (s,2H), 8.29 (s, 1H), 7.97 (s, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.8Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 5.00 (t, J=5.1 Hz, 1H), 4.61-4.49 (m,2H), 4.38-4.23 (m, 3H), 3.84-3.74 (m, 2H), 3.14-2.99 (m, 2H), 2.06-1.93(m, 2H), 1.70-1.52 (m, 2H).

¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 159.4, 158.7, 157.3, 153.9, 153.1,146.3, 142.8, 140.4, 137.6, 135.1, 133.5, 119.2, 117.9, 106.9, 104.0,95.3, 59.7, 48.8, 46.2, 44.3, 31.1.

Example 936-(4-((5-chloro-2-((3-(2-hydroxypropyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

Step 1) 1-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol

To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (2.50 g, 12.6 mmol)in DMF (15 mL) were added 1-bromopropan-2-ol (3.35 g, 19.0 mmol) andcesium carbonate (6.23 g, 19.1 mmol). The mixture was stirred at 100° C.overnight and concentrated in vacuo. The residue was purified by asilica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the titlecompound as a pale yellow solid (1.10 g, 34.0%).

MS (ESI, pos.ion) m/z: 256.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆): δ (ppm) 8.43 (d, J=2.4 Hz, 1H), 8.43 (s, 1H),8.34 (d, J=2.0 Hz, 1H), 5.04 (d, J=4.9 Hz, 1H), 4.23 (dd, J=13.6, 3.7Hz, 1H), 4.14-4.09 (m, 1H), 4.08-4.02 (m, 1H), 1.08 (d, J=6.1 Hz, 3H);

¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) 148.0, 146.4, 144.2, 136.5, 129.8,113.2, 64.9, 50.8, 21.3.

Step 2)1-(6-((diphenylmethylene)amino)-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol

To a solution of 1-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol(1.10 g, 4.30 mmol) in toluene (15 mL) were added Xantphos (253.1 mg,0.4374 mmol), Pd₂(dba)₃ (396.8 mg, 0.4333 mmol), t-BuONa (620.3 mg,6.455 mmol) and diphenylmethanimine (1.21 g, 6.68 mmol). The mixture wasstirred at 100° C. under nitrogen atmosphere for 6 h and concentrated invacuo. The residue was purified by a silica gel column chromatography(MeOH/DCM (v/v)=1/25) to give the title compound as a brown solid (446.5mg, 29.2%).

MS (ESI, pos.ion) m/z: 357.2 [M+H]⁺.

Step 3) 1-(6-amino-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol

To a solution of1-(6-((diphenylmethylene)amino)-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol(446.5 mg, 1.246 mmol) in THF (10 mL) was added HCl aqueous solution(1.0 mL, 12 mmol). The mixture was stirred at rt for 1 h andconcentrated in vacuo. The mixture was neutralized to pH=8 withsaturated NaHCO₃ aqueous solution and concentrated in vacuo. The residuewas purified by a flash column chromatography (MeOH/DCM (v/v)=1/10) togive the title compound as a brown solid (166.6 mg, 69.6%).

MS (ESI, pos.ion) m/z: 193.2 [M+H]⁺.

Step 3)6-(4-((5-chloro-2-((3-(2-hydroxypropyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile

To a solution of 1-(6-amino-3H-imidazo[4,5-b]pyridin-3-yl)propan-2-ol(166.6 mg, 0.8667 mmol) in 1,4-dioxane (15 mL) were added6-(4-((2,5-dichloropyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile(200.0 mg, 0.5711 mmol), Pd(OAc)₂ (15.2 mg, 0.0677 mmol), BINAP (36.8mg, 0.0591 mmol) and cesium carbonate (280.3 mg, 0.8603 mmol). Themixture was stirred at 100° C. for 3 h and concentrated in vacuo. Theresidue was purified by a flash column chromatography (MeOH/DCM(v/v)=1/25) to give the title compound as a pale yellow solid (100.0 mg,34.6%).

MS (ESI, pos.ion) m/z: 506.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 506.1934 [M+H]⁺, calculated value forC₂₃H₂₅ClN₁₁O [M+H]⁺ is 506.1927;

¹H NMR (600 MHz, DMSO-d₆): δ (ppm) 9.43 (s, 1H), 8.59 (d, J=1.9 Hz, 1H),8.39 (s, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.87 (d, J=9.7 Hz, 1H), 7.41(d, J=9.7 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 5.09 (d, J=4.5 Hz, 1H),4.62-4.52 (m, 2H), 4.44-4.35 (m, 1H), 4.23-4.16 (m, 1H), 4.09-3.98 (m,2H), 3.21-3.14 (m, 2H), 2.04-1.97 (m, 2H), 1.74-1.64 (m, 2H), 1.09 (d,J=5.8 Hz, 3H);

¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) 159.1, 158.7, 157.3, 153.8, 151.4,146.2, 138.0, 133.2, 131.5, 128.8, 126.8, 117.9, 111.6, 109.3, 104.3,65.6, 52.2, 47.9, 44.1, 30.9, 21.3.

Biological Testing

The LC/MS/MS system used in the analysis consists of an Agilent 1200Series vacuum degasser, binary pump, well-plate autosampler,thermostatted column compartment, the Agilent G6430 Triple QuadrupoleMass Spectrometer with an electrosprayionization (ESI) source.Quantitative analysis was carried out using MRM mode. The parameters forMRM transitions are in the Table A.

TABLE A MRM 490.2→383.1 Fragmentor 230 V CE 55 V Drying Gas Temp 350° C.Nebulize 0.28 MPa Drying Gas Flow 10 L/min

An Agilent XDB-C18, 2.1×30 mm, 3.5 μM column was used for the analysis.5 μL of the samples were injected. Analysis condition: The mobile phasewas 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B).The flow rate was 0.4 mL/min. And the gradient of Mobile phase was inthe Table B.

TABLE B Gradient of Time Mobile Phase B 0.5 min  5% 1.0 min 95% 2.2 min95% 2.3 min  5% 5.0 min stop

Alternatively, an Agilent 6330 series LC/MS/MS spectrometer equippedwith G1312A binary pumps, a G1367A autosampler and a G1314C UV detectorwere used in the analysis. An ESI source was used on the LC/MS/MSspectrometer. The analysis was done in positive ion mode as appropriateand the MRM transition for each analyte was optimized using standardsolution. A Capcell MP-C18 100×4.6 mm I.D., 5 uM column (Phenomenex,Torrance, Calif., USA) was used during the analysis. The mobile phasewas 5 mM ammonia acetate, 0.1% MeOH in water (A): 5 mM ammonia acetate,0.1% MeOH in acetonitrile (B) (70/30, v/v). The flow rate was 0.6mL/min. Column was maintained at ambient temperature. 20 μL of thesamples were injected.

Example A: Compound Stability in Human and Rat Liver Microsomes

Human or rat liver microsomes incubations were conducted in duplicate inpolypropylene tubes. The typical incubation mixtures consisted of humanor rat liver microsomes (0.5 mg protein/mL), compounds of interest (5μM) and NADPH (1.0 mM) in a total volume of 200 μL potassium phosphatebuffer (PBS, 100 mM, pH 7.4). Compounds were dissolved in DMSO anddiluted with PBS such that the final concentration of DMSO was 0.05%.The enzymatic reactions were commenced with the addition of proteinafter a 3-min preincubation and incubated in a water bath open to theair at 37° C. Reactions were terminated at various time points (0, 5,10, 15, 30, 60 min) by adding equal volume of ice-cold acetonitrile. Thesamples were stored at 80° C. until LC/MS/MS assays.

The concentrations of compounds in the incubation mixtures of human orrat liver microsomes were determined by a LC/MS/MS method. The ranges ofthe linearity in the concentration range were determined for each testedcompounds.

A parallel incubation was performed using denatured microsomes as thenegative control, and reactions were terminated at various time points(0, 15, 60 min) after incubation at 37° C.

Dextromethorphan (70 μM) was selected as the positive control, andreactions were terminated at various time points (0, 5, 10, 15, 30, 60min) after incubation at 37° C. Both positive and negative controlsamples were included in each assay to ensure the integrity of themicrosomal incubation system.

Data Analysis

The concentrations of compounds in human or rat liver microsomeincubations were plotted as a percentage of the relevant zero time pointcontrol for each reaction. The in vivo CLint were extrapolated (ref.:Naritomi, Y.; Terashita, S.; Kimura, S.; Suzuki, A.; Kagayama, A.; andSugiyama, Y.; Prediction of human hepatic clearance from in vivo animalexperiments and in vitro metabolic studies with liver microsomes fromanimals and humans. Drug Metab. Dispos., 2001, 29: 1316-1324).

Exemplary results from selected compounds of the invention are listed inTable 2. The compounds disclosed herein exhibited desirable stabilitywhen the compounds were incubated in human and rat liver microsomes.

TABLE 2 Stability of selected compounds of the invention in human andrat liver microsomes Human Rat Example T_(1/2) CL_(int) T_(1/2) CL_(int)# (min) (mL/min/kg) (min) (mL/min/kg) Ex. 2 36.17 48.06 47.37 52.43 Ex.3 56.29 30.88 ∞ NT Ex. 4 22.27 78.06 32.94 75.40 Ex. 7 148.2 11.73 22.25111.63 Ex. 9 71.94 24.16 8.21 302.71 Ex. 11 330.4 5.26 5048 0.34 Ex. 12117.0 14.86 185.9 13.36 Ex. 13 21.77 79.85 106.6 23.30 Ex. 14 26.0566.73 10.71 231.91 Ex. 15 22.02 78.94 2.98 833.74 Ex. 17 44.05 39.468.22 302.27 Ex. 20 153.4 11.3 82.7 30.0 Ex. 22 388.0 4.5 213.1 11.7 Ex.25 61.05 28.47 45.23 54.91 Ex. 28 41.45 41.94 15.14 164.05 Ex. 29 43.8939.61 32.36 76.75 Ex. 30 125.7 13.83 80.54 30.84 Ex. 34 125.1 13.9028.40 87.45 Ex. 35 182.9 9.50 144.1 17.24 Ex. 39 120.7 14.4 245.9 10.1Ex. 40 360.8 4.8 55.58 44.7 Ex. 41 198.5 8.8 42.91 57.9 Ex. 43 23.5 74.143.2 57.5 Ex. 46 63.15 27.53 76.31 32.55 Ex. 47 107.9 16.11 27.77 89.44Ex. 48 37.03 46.94 55.66 44.62 Ex. 49 52.69 32.99 32.49 76.45 Ex. 5055.58 31.28 29.87 58.20 Ex. 51 31.64 54.9 33.96 73.1 Ex. 52 47.75 36.429.2 85.1 Ex. 54 8.516 204.1 3.915 634.4 Ex. 55 1371 1.3 340.2 7.3 Ex.56 47.67 36.5 48.76 50.9 Ex. 59 69.3 25.1 28.6 86.8 Ex. 60 15.6 111.73.4 731.6 Ex. 61 128.0 13.6 28.8 86.2 Ex. 62 191.5 9.1 33.0 75.3 Ex. 6440.3 43.2 10.0 249.1 Ex. 65 8.0 217.8 5.3 473.1 Ex. 66 25.6 67.9 36.268.5 Ex. 67 127.1 13.7 30.83 80.6 Ex. 68 10.6 164.0 19.03 130.5 Ex. 69496.1 3.5 170.3 14.6 Ex. 70 10.32 168.4 4.706 527.8 Ex. 71 18.93 91.85.67 438.0 Ex. 73 42.0 41.3 11.6 213.7 Ex. 74 >60 NT >60 NT Ex. 75 >60NT >60 NT Ex. 76 15.1 115.4 1.7 1442.3 Ex. 77 257 6.8 64.99 38.2 Ex. 7835.29 49.3 15.84 156.8 Ex. 79 196.3 8.9 485.6 5.1 Ex. 80 40.7 42.7 18.97130.9 Ex. 81 419 4.1 97.29 25.5 Ex. 83 15.13 114.9 12.89 192.7 Ex. 8532.51 53.5 23.48 105.8 Ex. 88 4720 0.4 188.4 13.2 NT: Not Test

Example B: Evaluation of Pharmacokinetics after Intravenous and OralAdministration of the Compounds Disclosed Herein in Mice, Rats, Dogs andMonkeys

The compounds disclosed herein are assessed in pharmacokinetic studiesin mice, rats, dogs or monkeys. The compounds are administered as awater solution, 2% HPMC+1% TWEEN®80 in water solution, 5% DMSO+5%solutol in saline, 4% MC suspension or capsule. For the intravenousadministration, the animals are generally given at about 0.5, 0.6, 1 or2 mg/kg dose. For the oral (p.o.) dosing, mice and rats are generallygiven 5 or 10 mg/kg dose, and dogs and monkeys are generally given 10mg/kg dose. The blood samples (0.3 mL) are drawn at 0.25, 0.5, 1.0, 2.0,3.0, 4.0, 6.0, 8.0, 12 and 24 h time points or 0.083, 0.25, 0.5, 1.0,2.0, 4.0, 6.0, 8.0 and 24 h time points and centrifuged at 3,000 or 4000rpm for 2 to 10 min. The plasma solutions are collected, and stored at20° C. or 70° C. until analyzed by LC/MS/MS as described above.

Exemplary study results from examples disclosed herein are listed inTable 3. The compounds disclosed herein exhibited optimizedpharmacokinetic properties with good absorption, desirable oralbioavailability (F) and half-life (T1/2) when the compounds wereadministered orally or intravenously.

TABLE 3 Pharmacokinetic profiles of selected compounds of the inventionin rats iv dosing Example dose T_(1/2) AUC_(last) Cl/F Vss F # (mg/kg)(h) (ng · h/mL) (L/h/kg) (L/kg) (%) Ex. 2 1 1.10 1960 0.51 0.73 50.2 Ex.4 1 0.73 909 1.14 1.05 35.1 Ex. 5 1 4.41 2340 0.43 0.56 42.7 Ex. 6 14.72 2690 0.38 0.76 71.0 Ex. 9 0.6 0.81 547 1.25 1.13 69.1 Ex. 17 1 0.60949 1.07 0.67 48.2 Ex. 18 0.5 0.59 638 0.79 0.50 79.4 Ex. 21 1 0.72 14200.71 0.84 37.0 Ex. 23 1 1.05 844 1.18 1.68 63.0 Ex. 28 1 0.56 1220 0.840.56 56.1 Ex. 29 1 0.66 751 1.34 1.16 38.5 Ex. 30 1 2.61 5130 0.17 0.61115.5 Ex. 32 1 1.53 2020 0.85 0.96 180.3 Ex. 34 1 1.20 1560 0.63 1.5346.9 Ex. 35 1 2.60 3110 0.32 0.53 57.6 Ex. 37 1 0.93 1460 0.69 0.83 47.8Ex. 39 1 4.65 2830 0.35 1.25 52.0 Ex. 46 1 1.01 3400 0.29 0.42 125.9 Ex.47 1 0.78 1490 0.70 0.87 143.6 Ex. 48 1 1.08 1510 0.67 0.89 79.4 Ex. 491 0.60 1540 0.65 0.56 79.6 Ex. 50 0.96 1.05 1210 0.85 1.17 51.8 Ex. 52 10.86 1090 0.91 0.96 34.1 Ex. 54 1 0.79 714 1.43 0.95 36.6 Ex. 67 1 1.451470 0.67 1.25 49.7 Ex. 68 1 1.34 1090 0.90 1.51 NT Ex. 69 1 0.94 7521.33 1.70 69.8 Ex. 70 1 0.94 860 1.16 1.39 23.5 Ex. 73 1 0.70 464 2.191.80 56.4 Ex. 77 1 0.843 1860 9.07 0.623 NT Ex. 78 1 0.986 1490 11.20.795 84.8 Ex. 79 1 0.762 1020 16.3 1.23 42.1 Ex. 81 1 1.33 1710 9.750.946 99.6 EX. 83 1 1.41 1830 0.56 0.65 38.6 EX. 88 1 0.539 1460 1.050.688 4.5 NT: Not Test

Example C: Kinase Activity Assay

The efficacy of the compounds disclosed herein as inhibitors of proteinkinases can be evaluated as follows.

General Description for Kinase Assays

Kinase assays can be performed by measurement of incorporation of γ-³³PATP into immobilized myelin basic protein (MBP). High binding white 384well plates (Greiner) are coated with MBP (Sigma # M-1891) by incubationof 60 μL well of 20 μg/mL MBP in Tris-buffered saline (TBS; 50 mM TrispH 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 h at 4° C. Plates are washed 3×with 100 μL TBS. Kinase reactions are carried out in a total volume of34 μL in kinase buffer (according to the need to make, for example, 5 mMHepes pH 7.6, 15 mM NaCl, 0.01% bovine gamma globulin (Sigma #1-5506),10 mM MgCl₂, 1 mM DTT, 0.02% TritonX-100). Compound dilutions areperformed in DMSO and added to assay wells to a final DMSO concentrationof 1%. Each data point is measured in duplicate, and at least twoduplicate assays are performed for each individual compounddetermination. Enzyme is added to final concentrations of 10 nM or 20nM, for example. A mixture of unlabeled ATP and γ-³³P ATP is added tostart the reaction (2×10⁶ cpm of γ-³³P ATP per well (3000 Ci/mmole) and10 μM unlabeled ATP, typically. The reactions are carried out for 1 hourat room temperature with shaking. Plates are washed 7× with TBS,followed by the addition of 50 μL well scintillation fluid (Wallac).Plates are read using a Wallac Trilux counter. This is only one formatof such assays; various other formats are possible, as known to oneskilled in the art.

The above assay procedure can be used to determine the IC₅₀ forinhibition and/or the inhibition constant, K_(i). The IC₅₀ is defined asthe concentration of compound required to reduce the enzyme activity by50% under the condition of the assay. The IC₅₀ value is estimated bypreparing a 10 point curve using a ½ log dilution series (for example, atypical curve may be prepared using the following compoundconcentrations: 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM,0.001 μM, 0.0003 μM and 0 μM).

Kianse General Assay Protocol

JAK1 (h)

JAK1 (h) is incubated with 20 mM Tris/HCl pH 7.5, 0.2 mM EDTA, 500 μMGEEPLYWSFPAKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, 10 μM or K_(M) values). The reaction is initiatedby the addition of the MgATP mix. After incubation for 40 minutes atroom temperature, the reaction is stopped by the addition of 3%phosphoric acid solution. 10 μL of the reaction is then spotted onto aP30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

JAK2 (h)

JAK2 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μMKTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10 mM MgAcetate and [γ-³³P-ATP](specific activity approx. 500 cpm/pmol, 10 μM or K_(M) values). Thereaction is initiated by the addition of the MgATP mix. After incubationfor 40 minutes at room temperature, the reaction is stopped by theaddition of 3% phosphoric acid solution. 10 μL of the reaction is thenspotted onto a P30 filtermat and washed three times for 5 minutes in 75mM phosphoric acid and once in methanol prior to drying andscintillation counting.

JAK3 (h)

JAK3 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 μMGGEEEEYFELVKKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, 10 μM or K_(M) values). The reaction is initiatedby the addition of the MgATP mix. After incubation for 40 minutes atroom temperature, the reaction is stopped by the addition of 3%phosphoric acid solution. 10 μL of the reaction is then spotted onto aP30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

TYK2 (h)

TYK2 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μMGGMEDIYFEFMGGKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, 10 μM or K_(M) values). The reaction is initiatedby the addition of the MgATP mix. After incubation for 40 minutes atroom temperature, the reaction is stopped by the addition of 3%phosphoric acid solution. 10 μL of the reaction is then spotted onto aP30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

FLT3 (h)

FLT3 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μMEAIYAAPFAKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activity approx.500 cpm/pmol, 10 μM or K_(M) values). The reaction is initiated by theaddition of the MgATP mix. After incubation for 40 minutes at roomtemperature, the reaction is stopped by the addition of 3% phosphoricacid solution. 10 μL of the reaction is then spotted onto a P30filtermat and washed three times for 5 minutes in 75 mM phosphoric acidand once in methanol prior to drying and scintillation counting.

FLT4 (h)

FLT4 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μMGGEEEEYFELVKKKK, 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, 10 μM or K_(M) values). The reaction is initiatedby the addition of the MgATP mix. After incubation for 40 minutes atroom temperature, the reaction is stopped by the addition of 3%phosphoric acid solution. 10 μL of the reaction is then spotted onto aP30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

Aurora-A (h)

Aurora-A (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 200 μMLRRASLG (Kemptide), 10 mM MgAcetate and [γ-³³P-ATP] (specific activityapprox. 500 cpm/pmol, 10 μM or K_(M) values). The reaction is initiatedby the addition of the MgATP mix. After incubation for 40 minutes atroom temperature, the reaction is stopped by the addition of 3%phosphoric acid solution. 10 μL of the reaction is then spotted onto aP30 filtermat and washed three times for 5 minutes in 75 mM phosphoricacid and once in methanol prior to drying and scintillation counting.

Aurora-B (h)

Aurora-B (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 μMAKRRRLSSLRA, 10 mM MgAcetate and [γ-³³PATP] (specific activity approx.500 cpm/pmol, 10 μM or K_(M) values). The reaction is initiated by theaddition of the MgATP mix. After incubation for 40 minutes at roomtemperature, the reaction is stopped by the addition of a 3% phosphoricacid solution. 10 μL of the reaction is then spotted onto a P30filtermat and washed three times for 5 minutes in 75 mM phosphoric acidand once in methanol prior to drying and scintillation counting.

The kinase assays described herein were performed at Millipore UK Ltd,Dundee Technology Park, Dundee DD2 1SW, UK.

Alternatively, the kinase activities of the compounds can be measuredusing KINOMEscan™, which is based on a competition binding assay thatquantitatively measures the ability of a compound to compete with animmobilized, active-site directed ligand. The assay was performed bycombining three components: DNA-tagged kinase; immobilized ligand; and atest compound. The ability of the test compound to compete with theimmobilized ligand was measured via quantitative PCR of the DNA tag.

For most assays, kinase-tagged T7 phage strains were prepared in an E.coli host derived from the BL21 strain. E. coli were grown to log-phaseand infected with T7 phage and incubated with shaking at 32° C. untillysis. The lysates were centrifuged and filtered to remove cell debris.The remaining kinases were produced in HEK-293 cells and subsequentlytagged with DNA for qPCR detection. Streptavidin-coated magnetic beadswere treated with biotinylated small molecule ligands for 30 minutes atroom temperature to generate affinity resins for kinase assays. Theliganded beads were blocked with excess biotin and washed with blockingbuffer (SEABLOCK™ (Pierce), 1% BSA, 0.05% TWEEN®20, 1 mM DTT) to removeunbound ligand and to reduce nonspecific binding. Binding reactions wereassembled by combining kinases, liganded affinity beads, and testcompounds in 1× binding buffer (20% SEABLOCK™, 0.17×PBS, 0.05% TWEEN®20,6 mM DTT). All reactions were performed in polystyrene 96-well plates ina final volume of 0.135 mL. The assay plates were incubated at roomtemperature with shaking for 1 hour and the affinity beads were washedwith wash buffer (1×PBS, 0.05% TWEEN®20). The beads were thenre-suspended in elution buffer (1×PBS, 0.05% TWEEN®20, 0.5 μMnon-biotinylated affinity ligand) and incubated at room temperature withshaking for 30 minutes. The kinase concentration in the eluates wasmeasured by qPCR.

The kinase activity assays described herein can be performed usingKINOMEscan™ Profiling Service at DiscoveRx Corporation, 42501 Albrae St.Fremont, Calif. 94538, USA.

Exemplary assay results from compounds disclosed herein are listed inTable 4 and Table 5. The compounds disclosed herein displayed inhibitoryactivities against JAK1, JAK2, JAK3, TYK2, Aurora-A, Aurora-B, FLT4 andFLT3 kinases in the corresponding kinase assays. Especially, thosecompounds shown potent inhibitory activities against JAK1 and JAK2.

Table 4 listed the IC₅₀s of some compounds described herein in the JAK1,JAK2 and Aurora-A kinase assays; Table 5 listed the IC₅₀s of somecompounds described herein in the JAK3, TYK2, Aurora-B, FLT4 and FLT3kinase assays.

TABLE 4 IC_(50S) of compounds described herein in the JAK1, JAK2 andAurora-A kinase assays IC₅₀ (nM) JAK1 JAK2 Aurora-A Example # (h) (h)(h) Ex. 2 1 3 NT Ex. 3 0.6 2 NT Ex. 12 0.4 16 281 Ex. 13 0.5 NT NT Ex.14 3 NT NT Ex. 16 0.3 NT NT Ex. 20 0.5 NT NT Ex. 21 <0.3 NT NT Ex. 25 3NT NT Ex. 27 <0.3 10 467 Ex. 28 0.5 NT NT Ex. 30 0.9 10 630 Ex. 32 0.5 7662 Ex. 38 0.9 41 440 Ex. 39 0.6 5 708 Ex. 40 <0.3 1 119 Ex. 42 <0.3 231461 Ex. 43 <0.3 NT NT Ex. 46 <0.3 1 187 Ex. 47 <0.3 7 116 Ex. 48 <0.30.7 315 Ex. 55 0.9 14 >300 Ex. 56 0.5 15 >300 Ex. 57 0.9 5 >300 Ex. 580.8 27 >300 Ex. 59 0.7 NT NT Ex. 60 0.4 4 216 Ex. 61 <0.3 1 113 Ex. 620.4 2 NT Ex. 63 0.4 NT NT Ex. 64 0.5 NT NT Ex. 65 0.9 NT NT Ex. 66 0.3NT NT Ex. 67 0.6 39 987 Ex. 68 0.3 3 NT Ex. 69 0.5 2 40 Ex. 70 0.5 8 NTEx. 71 0.9 NT NT Ex. 73 1 5 NT Ex. 74 0.7 4 NT Ex. 75 1 8 NT Ex. 76 0.5NT NT Ex. 77 0.7 17 699 Ex. 78 1 10 561 Ex. 79 1 102 NT Ex. 80 0.6 NT NTEx. 81 <0.3 NT NT Ex. 85 0.3 17 NT Ex. 89 2 NT NT NT: Not Test

TABLE 5 IC_(50S) of some compounds described herein in the JAK3, TYK2,Aurora-B, FLT4 and FLT3 kinase assays IC₅₀ (nM) JAK3 TYK2 Aurora-B FLT3Example # (h) (h) (h) (h) Ex. 2 NT NT 46 287 Ex. 3 NT NT 102 591 Ex. 12NT NT 115 667 Ex. 30 127 4 NT NT Ex. 32 60 2 NT NT Ex. 55 291 NT 20095(Flt4) Ex. 60 NT NT 216 NT Ex. 61 5 0.9 50 20(Flt4) Ex. 62 NT NT 48 NTEx. 67 542 8 793 113(Flt4) Ex. 68 NT NT 223 NT Ex. 69 5 0.7 45 15(Flt4)Ex. 70 NT NT 125 NT Ex. 73 112 NT 13 87(Flt4) Ex. 74 64 NT 46 57(Flt4)Ex. 75 202 NT 184 202(Flt4) Ex. 77 353 9 132 166(Flt4) Ex. 78 344 5 185117(Flt4) Ex. 85 NT NT 163 NT NT: Not Test

Example D: Inhibitory Effect of Compounds on Topical PMA-Induced AcuteAtopic Dermatitis in ICR Mice

ICR female mice (20-30 g), five mice or nine mice/group, were used inthis study. Five micrograms of PMA (phorbol 12-myristate 13-acetate) in20 μL of ethanol was applied topically to the anterior and posteriorsurface of the right ear of each mouse. Twenty microliters of vehicle(ethanol/acetone (WV)=1/1); 0.3 mg of EX. 68 (in 204); EX. 76, EX. 50,EX. 92 or EX. 65 (0.3 mg in 204) were administrated to the same areas 30minutes before and 15 minutes after PMA application. The thickness ofright ears of each mouse was measured 6 hours after PMA stimulation. Earweight of right ears of each mouse was weighed with analytical balanceEach value represents the Mean±Sem. Statistical significance comparedwith model groups (*P<0.05; **P<0.01). Tables 5-1, 5-2 and 5-3 listedthe inhibitory effect on PMA-induced increase in mouse ear thickness andweight. The compounds of the present invention have a good inhibitoryeffect on PMA-induced increase in mouse ear thickness and weight.

TABLE 5-1 Inhibitory effect of Example 68 on topical PMA-Induced AcuteAtopic Dermatitis in ICR mice ICR thickness Weight dose mice thicknessInhibition Weight Inhibition Group mg/ear/bid (N) (mm) ratio (mg) ratiovehicle 0 5   0.203 ± 0.003**  100%  13.60 ± 0.51*  100% model 0 9 0.323± 0.009   0% 36.89 ± 1.14   0% EX. 68 0.3 9   0.219 ± 0.007** 86.6% 18.11 ± 1.14* 80.6% Statistical significance compared with model group(*P < 0.05; **P < 0.01)

TABLE 5-2 Inhibitory effect of Examples 76 and 50 on topical PMA-InducedAcute Atopic Dermatitis in ICR mice ICR thickness Weight dose micethickness Inhibition Weight Inhibition Group mg/ear/bid (N) (mm) ratio(mg) ratio vehicle 0 5   0.202 ± 0.006**   100%   14.200 ± 0.735**  100% model 0 9 0.426 ± 0.011    0% 32.556 ± 1.345    0% EX. 76 0.3 9  0.252 ± 0.018** 77.86%   20.000 ± 1.323** 68.40% EX. 50 0.3 9   0.321± 0.022** 46.89%   25.222 ± 1.998** 39.95% Statistical significancecompared with model group (*P < 0.05; **P < 0.01)

TABLE 5-3 Inhibitory effect of Examples 92 and 65 on topical PMA-InducedAcute Atopic Dermatitis in ICR mice ICR thickness Weight dose micethickness Inhibition Weight Inhibition Group mg/ear/bid (N (mm) ratio(mg) ratio vehicle 0 4 0.214 ± 0.007 **   100% 16.250 ± 0.764 **   100%model 0 9 0.477 ± 0.017    0% 35.000 ± 1.716    0% EX. 92 0.3 9 0.319 ±0.027** 60.03% 21.444 ± 1.952** 72.30% EX. 65 0.3 9 0.374 ± 0.022**38.95% 26.333 ± 1.958* 46.22% Statistical significance compared withmodel group (*P < 0.05; **P < 0.01)

Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive and theinvention is not be limited to the details given herein, but may bemodified within the scope and equivalents of the appended claims. Allpublications and patents cited herein are incorporated by reference.

What is claimed is:
 1. A compound having Formula (I):

or a stereoisomer, a tautomer, an N-oxide, a solvate, or apharmaceutically acceptable salt thereof, wherein: W is a 4-7 memberedsaturated monocyclic heterocyclylene or saturated monocyclic C₅-C₇carbocyclylene, wherein W is optionally substituted by 1, 2, 3, 4 or 5R² groups; T is C₆-C₁₂ aryl or 5-12 membered heteroaryl, wherein T isoptionally substituted by 1, 2, 3, 4 or 5 R³ groups; A is an optionallysubstituted 9-membered heteroaryl group, having Formula (A-1), (A-2),(A-3), (A-4), (A-5) or (A-6):

wherein each V₁ and V₂ is independently CR⁴ or N; each U₁, U₂ and U₃ isindependently CR⁴ or N; each of U₄ and U₆ is independently CR⁴, N, NR⁵,O or S; U₅ is independently CR⁴, O or S; wherein at least one of V₁, V₂,U₃, U₄, U₅ and U₆ is not CR⁴; Z is H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl or3-12 membered heterocyclyl, wherein each of the C₁-C₁₂, alkyl, C₃-C₁₂cycloalkyl and 3-12 membered heterocyclyl is optionally substituted by1, 2, 3, 4 or 5 R⁹ groups; R¹ is H, F, Cl, Br, I, NO₂, N₃, CN, C₁-C₁₂alkyl, C₁-C₁₂ heteroalkyl, C₃-C₁₂ cycloalkyl or 3-12 memberedheterocyclyl, wherein each of the C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl,C₃-C₁₂ cycloalkyl and 3-12 membered heterocyclyl is optionallysubstituted by 1, 2 or 3 R⁹ groups; each R² and R³ is independently F,Cl, Br, I, NO₂, N₃, CN, OH, C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, —(C₁-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl), —(C₁-C₄ alkylene)-(5-12membered heteroaryl), —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)C(═O)R⁸, —(CR⁶R⁷)_(n)OC(═O)R⁸, —O(CR⁶R⁷)_(n)—R^(c),—(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —N(R^(c))C(═O)NR^(a)R^(b),—N(R^(c))S(═O)_(m)NR^(a)R^(b), —C(═O)N(R^(c))C(═O)R⁸,—(CR⁶R⁷)_(n)S(═O)_(m)R⁸, —N(R^(c))S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₁₂ alkyl,C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12membered heteroaryl, —(C₁-C₄ alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄alkylene)-(3-12 membered heterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl)and —(C₁-C₄ alkylene)-(5-12 membered heteroaryl) is optionallyindependently substituted by 1, 2, 3, 4 or 5 R⁹ groups; each R⁴ isindependently H, F, Cl, Br, I, NO₂, N₃, CN, C₁-C₁₂ alkyl, C₁-C₁₂heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl, 5-12 memberedheteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)C(═O)R⁸, —(CR⁶R⁷)_(n)OC(═O)R⁸, —O(CR⁶R⁷)_(n)—R^(c),—(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —N(R^(c))C(═O)NR^(a)R^(b),—N(R^(c))S(═O)_(m)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸,—N(R^(c))S(═O)_(m)R⁸ or —(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), or twoadjacent R⁴ taken together with the carbon atoms to which they areattached form a C₃-C₁₂ carbocycle or 3-12 membered heterocycle, whereineach of the C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12membered heterocyclyl, 5-12 membered heteroaryl, C₃-C₁₂ carbocycle and3-12 membered heterocycle is optionally independently substituted by 1,2, 3, 4 or 5 R⁹ groups; each R⁵ is independently absent, or H, C₁-C₁₂alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl,5-12 membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)C(═O)R⁸, —(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —(CR⁶R⁷)_(n)S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein each of the C₁-C₁₂ alkyl,C₁-C₁₂ heteroalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl and 5-12membered heteroaryl is optionally independently substituted by 1, 2 or 3R⁹ groups; each R⁶ and R⁷ is independently H, F, Cl, Br, I, NO₂, N₃, CN,C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, C₆-C₁₂ aryl, 3-12 membered heterocyclyl or 5-12 memberedheteroaryl, or R⁶ and R⁷ taken together with the carbon atom to whichthey are attached form a C₃-C₁₂ carbocycle or 3-12 membered heterocycle,wherein each of the C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 memberedheterocyclyl, 5-12 membered heteroaryl, C₃-C₁₂ carbocycle and 3-12membered heterocycle is optionally independently substituted by 1, 2 or3 R⁹ groups; each R⁸ is independently C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12membered heterocyclyl, 5-12 membered heteroaryl, —(C₁-C₄alkylene)-(C₃-C₁₂ cycloalkyl), —(C₁-C₄ alkylene)-(3-12 memberedheterocyclyl), —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl) or —(C₁-C₄alkylene)-(5-12 membered heteroaryl), wherein each R⁸ is optionallysubstituted by 1, 2 or 3 R⁹ groups; each R⁹ is independently F, Cl, Br,I, CN, NO₂, N₃, —OH, —NH₂, C₁-C₁₂, alkyl, C₁-C₁₂ heteroalkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, 3-12 memberedheterocyclyl, 5-12 membered heteroaryl, —NH(C₁-C₁₂ alkyl),—NH(CH₂)_(n)—(C₃-C₁₂ cycloalkyl), —NH(CH₂)_(n)—(C₆-C₁₂ aryl),—NH(CH₂)_(n)-(3-12 membered heterocyclyl), —NH(CH₂)_(n)-(5-12 memberedheteroaryl), —N(C₁-C₁₂ alkyl)₂, —N[(CH₂)_(n)—(C₃-C₁₂ cycloalkyl)]₂,—N[(CH₂)_(n)—(C₆-C₁₂ aryl)]₂, —N[(CH₂)_(n)-(3-12 memberedheterocyclyl)]₂, —N[(CH₂)_(n)-(5-12 membered heteroaryl)]₂, —O(C₁-C₁₂alkyl), —O(CH₂)_(n)—(C₃-C₁₂cycloalkyl), —O(CH₂)_(n)—(C₆-C₁₂ aryl),—O(CH₂)_(n)-(3-12 membered heterocyclyl) or —O(CH₂)_(n)-(5-12 memberedheteroaryl); each R^(a), R^(b) and R^(c) is independently H, C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, —(C₁-C₄ alkylene)-(C₃-C₆ cycloalkyl), 4-7 memberedheterocyclyl, —(C₁-C₄ alkylene)-(4-7 membered heterocyclyl), C₆-C₁₂aryl, —(C₁-C₄ alkylene)-(C₆-C₁₂ aryl), 5-12 membered heteroaryl or—(C₁-C₄ alkylene)-(5-12 membered heteroaryl), or R^(a) and R^(b) takentogether with the nitrogen atom to which they are attached form a 4-7membered heterocycle, wherein each of the C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, —(C₁-C₄alkylene)-(C₃-C₆ cycloalkyl), 4-7 membered heterocyclyl, —(C₁-C₄alkylene)-(4-7 membered heterocyclyl), C₆-C₁₂ aryl, —(C₁-C₄alkylene)-(C₆-C₁₂ aryl), 5-12 membered heteroaryl, —(C₁-C₄alkylene)-(5-12 membered heteroaryl) and 4-7 membered heterocycle isoptionally independently substituted by 1, 2, 3 or 4 substitutentsindependently selected from F, Cl, Br, CN, N₃, —OH, —NH₂, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ alkylamino; each n isindependently 0, 1, 2, 3 or 4; and each m is independently 1 or
 2. 2.The compound according to claim 1, wherein W is a saturated monocyclicheterocyclylene derived from one of the following heterocycliccompounds:

and wherein W is optionally substituted by 1, 2 or 3 R² groups.
 3. Thecompound according to claim 1, wherein W is:

and wherein W is optionally substituted by 1, 2 or 3 R² groups.
 4. Thecompound according to claim 1, wherein T is phenyl or 5-6 memberedheteroaryl, wherein T is optionally substituted by 1, 2, 3 or 4 R³groups.
 5. The compound according to claim 1, wherein T is phenyl,pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyridazinyl, pyrazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, imidazolyl, isoxazolyl,oxazolyl, pyrrolyl, thiazolyl, isothiazolyl, tetrazolyl, triazolyl,thienyl, pyrazolyl, oxadiazolyl, thiadiazolyl or triazinyl, wherein T isoptionally substituted by 1, 2 or 3 R³ groups.
 6. The compound accordingto claim 1, wherein A is:

wherein each CH in A is optionally independently substituted by a R⁴group; each NH in A is optionally independently substituted by a R⁵group.
 7. The compound according to claim 1, wherein Z is H, C₁-C₆alkyl, C₃-C₆ cycloalkyl or 4-7 membered heterocyclyl, wherein each ofthe C₁-C₆ alkyl, C₃-C₆ cycloalkyl and 4-7 membered heterocyclyl isoptionally substituted by 1, 2 or 3 R⁹ groups.
 8. The compound accordingclaim 1, wherein Z is H, methyl, ethyl, n-propyl, i-propyl, cyclopropylor cyclobutyl.
 9. The compound according to claim 1, wherein R¹ is H, F,Cl, Br, NO₂, N₃, CN, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₃-C₆ cycloalkyl or4-7 membered heterocyclyl, wherein each of the C₁-C₄ alkyl, C₁-C₄heteroalkyl, C₃-C₆ cycloalkyl and 4-7 membered heterocyclyl isoptionally substituted by 1, 2 or 3 R⁹ groups.
 10. The compoundaccording to claim 1, wherein R² and/or R³ is independently F, Cl, Br,NO₂, N₃, CN, OH, C₁-C₄ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 memberedheterocyclyl, 5-6 membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c),—(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)OC(═O)R⁸,—(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸, —(CR⁶R⁷)_(n)C(═O)OR^(c),—(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b), —(CR₆R₇)_(n)S(═O)_(m)R⁸,—N(R^(c))S(═O)_(m)R⁸ or —(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), wherein eachof the C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 memberedheterocyclyl and 5-6 membered heteroaryl is optionally independentlysubstituted by 1, 2 or 3 R⁹ groups.
 11. The compound according to claim1, wherein each R⁴ is independently H, F, Cl, Br, NO₂, N₃, CN, C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6membered heteroaryl, —(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b),—(CR⁶R⁷)_(n)OC(═O)R⁸, —(CR⁶R⁷)_(n)—N(R^(c))C(═O)R⁸,—(CR⁶R⁷)_(n)C(═O)OR^(c), —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b),—(CR⁶R⁷)_(n)S(═O)_(m)R⁸, —N(R^(c))S(═O)_(m)R⁸ or—(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), or two adjacent R⁴ taken together withthe carbon atoms to which they are attached form a C₃-C₆ carbocycle or4-7 membered heterocycle, wherein each of the C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl,C₃-C₆ carbocycle and 4-7 membered heterocycle is optionallyindependently substituted by 1, 2 or 3 R⁹ groups.
 12. The compoundaccording to claim 1, wherein each R⁴ is independently H, F, Cl, Br, N₃,CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃,—CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,—(CR⁶R⁷)_(n)—C(═O)OR^(c) or —(CR⁶R⁷)_(n)—C(═O)NR^(a)R^(b), or twoadjacent R⁴ taken together with the carbon atoms to which they areattached form a C₄-C₆ carbocycle or 4-7 membered heterocycle, whereineach of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH,—CH₂CH(OH)CH₃, —CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₄-C₆carbocycle and 4-7 membered heterocycle is optionally independentlysubstituted by 1, 2 or 3 R⁹ groups.
 13. The compound according to claim1, wherein each R⁵ is independently absent, or H, C₁-C₆ alkyl, C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl,—(CR⁶R⁷)_(n)—OR^(c), —(CR⁶R⁷)_(n)—NR^(a)R^(b), —(CR⁶R⁷)_(n)OC(═O)R⁸,—(CR⁶R⁷)_(n)C(═O)OR^(c), —(CR⁶R⁷)_(n)C(═O)NR^(a)R^(b),—(CR⁶R⁷)_(n)S(═O)_(m)R⁸ or —(CR⁶R⁷)_(n)S(═O)_(m)NR^(a)R^(b), whereineach of the C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 memberedheterocyclyl and 5-6 membered heteroaryl is optionally independentlysubstituted by 1, 2 or 3 R⁹ groups.
 14. The compound according to claim1, wherein each R⁵ is independently absent, or H, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, —CH₂OH,—CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃, —CH₂C(CH₃)₂OH,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl,pyrrolidinyl, morpholinyl, piperazinyl, —(CR⁶R⁷)_(n)C(═O)OR^(c) or—(CR⁶R⁷)—C(═O)NR^(a)R^(b), wherein each of the methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, —CH₂OH, —CH₂CH₂OH,—CH(OH)CH₃, —C(CH₃)₂OH, —CH₂CH(OH)CH₃, —CH₂C(CH₃)₂OH, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl,morpholinyl and piperazinyl is optionally independently substituted by1, 2 or 3 R⁹ groups.
 15. The compound according to claim 1, wherein eachR⁶ and R⁷ is independently H, F, Cl, Br, CN, C₁-C₄ alkyl, C₁-C₄heteroalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7membered heterocyclyl or 5-6 membered heteroaryl, or R⁶ and R⁷ takentogether with the carbon atom to which they are attached form a C₃-C₆carbocycle or 4-7 membered heterocycle, wherein each of the C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl,phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, C₃-C₆carbocycle and 4-7 membered heterocycle is optionally independentlysubstituted by 1, 2 or 3 R⁹ groups.
 16. The compound according to claim1, each R⁸ is independently C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 memberedheterocyclyl, 5-6 membered heteroaryl, —(C₁-C₃ alkylene)-(C₃-C₆cycloalkyl), —(C₁-C₃ alkylene)-(4-7 membered heterocyclyl), —(C₁-C₃alkylene)-phenyl or —(C₁-C₃ alkylene)-(5-6 membered heteroaryl), whereineach R⁸ is optionally substituted by 1, 2 or 3 R⁹ groups.
 17. Thecompound according to claim 1, wherein each R⁹ is independently F, Cl,Br, CN, N₃, —NH₂, —OH, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6membered heteroaryl, —NH(C₁-C₆ alkyl), —NH(CH₂)_(n)—(C₃-C₆ cycloalkyl),—NH(CH₂)_(n)-phenyl, —NH(CH₂)_(n)-(4-7 membered heterocyclyl),—NH(CH₂)_(n)-(5-6 membered heteroaryl), —N(C₁-C₆ alkyl)₂,—N[(CH₂)_(n)—(C₃-C₆ cycloalkyl)]₂, —N[(CH₂)_(n)-phenyl]₂,—N[(CH₂)_(n)-(4-7 membered heterocyclyl)]₂, —N[(CH₂)_(n)-(5-6 memberedheteroaryl)]₂, —O(CH₂)_(n)—(C₃-C₆ alkyl), —O(CH₂)_(n)—(C₃-C₆cycloalkyl), —O(CH₂)_(n)-phenyl, —O(CH₂)_(n)—(4-7 membered heterocyclyl)or —O(CH₂)_(n)-(5-6 membered heteroaryl).
 18. The compound according toclaim 1, wherein each R^(a), R^(b) and R^(c) is independently H, methyl,ethyl, n-propyl, isopropyl, n-butyl, C₁-C₄ heteroalkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-6membered heterocyclyl, phenyl, 5-6 membered heteroaryl, —(C₁-C₂alkylene)-(C₃-C₆ cycloalkyl), alkylene)-(4-7 membered heterocyclyl),—(C₁-C₂ alkylene)-phenyl or —(C₁-C₂ alkylene)-(5-6 membered heteroaryl),or R^(a) and R^(b) taken together with the nitrogen atom to which theyare attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl,wherein each of the methyl, ethyl, n-propyl, isopropyl, n-butyl, C₁-C₄heteroalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, —(C₁-C₂ alkylene)-(C₃-C₆ cycloalkyl), 4-6membered heterocyclyl, alkylene)-(4-7 membered heterocyclyl), phenyl,—(C₁-C₂ alkylene)-phenyl, 5-6 membered heteroaryl, alkylene)-(5-6membered heteroaryl), azetidinyl, pyrrolidinyl, piperidinyl andmorpholinyl is optionally independently substituted by 1, 2 or 3substitutents independently selected from F, C₁, CN, N₃, —OH, —NH₂,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ alkylamino.
 19. Thecompound according to claim 1 having one of the following structures:

or a stereoisomer, a tautomer, an N-oxide, a solvate, or apharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising the compound of claim 1, and a pharmaceuticallyacceptable excipient, carrier, adjuvant, vehicle or a combinationthereof.
 21. The pharmaceutical composition of claim 20 furthercomprising a therapeutic agent selected from the group consisting ofchemotherapeutic agents, anti-proliferative agents, phosphodiesterase 4(PDE4) inhibitors, β₂-adrenoreceptor agonists, corticosteroids,non-steroidal GR agonists, anticholinergic agents, antihistamines,anti-inflammatory agents, immunosuppressants, immunomodulators, agentsfor treating atherosclerosis, agents for treating pulmonary fibrosis andcombinations thereof.
 22. A method of treating or lessening the severityof a protein kinase-mediated disease in a patient by administering tothe patient with the compound of claim 1, wherein the proteinkinase-mediated disease is a JAK-mediated disease, a FLT3-mediateddisease, an Aurora-mediated disease, dermatitis, lung cancer,polycythemia vera, essential thrombocytosis, myelofibrosis, chronicmyelogenous leukemia (CML), acute myeloid leukemia (AML), acutelymphocytic leukemia (ALL), psoriasis or rheumatoid arthritis.
 23. Amethod of treating or lessening the severity of a proteinkinase-mediated disease in a patient by administering to the patientwith the pharmaceutical composition of claim 20, wherein the proteinkinase-mediated disease is a JAK-mediated disease, a FLT3-mediateddisease, an Aurora-mediated disease, dermatitis, lung cancer,polycythemia vera, essential thrombocytosis, myelofibrosis, chronicmyelogenous leukemia (CML), acute myeloid leukemia (AML), acutelymphocytic leukemia (ALL), psoriasis or rheumatoid arthritis.
 24. Amethod of inhibiting the activity of a protein kinase with the compoundof claim 1, wherein the protein kinase is JAK kinase, FLT3 kinase,Aurora kinase or a combination thereof.
 25. A method of inhibiting theactivity of a protein kinase with the pharmaceutical composition ofclaim 20, wherein the protein kinase is JAK kinase, FLT3 kinase, Aurorakinase or a combination thereof.